Changes in cerebral glucose metabolism at rest following hemicontusive spinal cord injury in mice: A whole-brain autoradiographic study

Changes in cerebral glucose metabolism at rest following hemicontusive spinal cord injury in mice: A whole-brain autoradiographic study | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Changes in cerebral glucose metabolism at rest following hemicontusive spinal cord injury in mice: A whole-brain autoradiographic study Zhuo Wang , Camelia Danilov , Dilan Setiya , View ORCID Profile Daniel P. Holschneider doi: https://doi.org/10.1101/2025.10.01.679887 Zhuo Wang a Department of Psychiatry and Behavioral Sciences, University of Southern California , Los Angeles, California, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Camelia Danilov b Department of Neurological Surgery, University of Southern California , Los Angeles, California, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dilan Setiya c Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel P. Holschneider a Department of Psychiatry and Behavioral Sciences, University of Southern California , Los Angeles, California, USA d Department of Neurology, University of Southern California , Los Angeles, California, USA e Department of Biomedical Engineering, University of Southern California , Los Angeles, California, USA f Graduate Program in Neuroscience, University of Southern California , Los Angeles, California, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Daniel P. Holschneider For correspondence: holschne{at}usc.edu Abstract Full Text Info/History Metrics Preview PDF ABSTRACT Spinal cord injury (SCI) disrupts brain-spinal cord communications and results in profound brain reorganization. Here, we apply high-resolution, voxel-based, whole-brain metabolic mapping using the [ 14 C]-2-deoxyglucose autoradiographic method in mice to assess functional brain reorganization in a subacute stage (1 week after SCI). Right moderate contusive injury at the cervical 5 level (C5) was confirmed by glial fibrillary acidic protein (GFAP) immunohistochemical staining. SCI compared to sham-lesioned animals showed significant motor deficits (grip strength, rotarod) alongside decreases in glucose uptake in sensorimotor regions of the cortex, basal ganglia, and thalamus, which receive monosynaptic afferents (the ventral posterolateral thalamic nucleus, VPL) or multi-synaptic afferents from the spinal cord (the primary somatosensory and motor cortices, caudate putamen). In contrast, regions in the limbic system (the amygdala, accumbens nucleus, lateral septum, and hippocampus) and in the cerebellum demonstrated increases in glucose uptake in SCI animals. Most of these effects were noted bilaterally, suggesting functional reorganization involving higher order neural circuits bilaterally. The current findings underscore the broadness of brain reorganization in the subacute stage following incomplete SCI. Functional whole-brain metabolic mapping provides a roadmap for future targeted studies examining neuroplastic mechanisms in search of new therapeutic strategies. INTRODUCTION Following spinal cord injury (SCI), the central nervous system undergoes significant reorganization not only in the spinal but also in the supraspinal circuits ( Solstrand Dahlberg et al ., 2018 ). After an incomplete SCI, intraspinal projection neurons can generate new “detour circuits” that transmit information onto the spinal cord from above to below the injury ( Murray et al ., 2010 ; Takeoka et al ., 2014 ) ( Filli & Schwab, 2015 ). Corticospinal tract fibers can regenerate, sprout, or reorganize to recover functional circuits alongside remaining neurons in the spinal cord ( Oudega & Perez, 2012 ). In addition, following SCI, the control of movement is not limited to the corticospinal tract fibers, but may also recruit other descending pathways such as the reticulospinal, rubrospinal, and tectospinal tracts ( Calderone et al ., 2024 ). Supraspinal reorganization is proposed to be the result of neuroplastic changes with complex spatial and temporal patterns following SCI, including acute changes in response to the damage of efferent fibers and deafferentation, as well as long-term changes involving retrograde neuronal degeneration, afferent fiber remodeling, and adaptation at the circuit level (see review ( Calderone et al ., 2024 )). Contributing plasticity includes the growth of new axonal branches ( Jain et al ., 2000 ; Fouad et al ., 2001 ; Weidner et al ., 2001 ; Vavrek et al ., 2006 ), synaptic remodeling ( Li et al ., 2004 ; Kim et al ., 2006 ), homeostatic synaptic plasticity, and changes in neuronal membrane characteristics such as sustained inward currents ( Harvey et al ., 2006 ) among others. Clinical and preclinical neuroimaging studies on SCI have advanced our understanding of structural (using computer tomographic imaging CT, magnetic resonance imaging MRI) and functional changes in the brain (using resting-state and task-related functional MRI). These studies demonstrate widespread changes in structure, regional activation, somatosensory and motor topographic maps, and inter-regional functional connectivity while details of these findings may vary depending on the type, severity, and stage of SCI (reviewed by Wang et al. 2019 , Nardone et al. 2013 ) ( Nardone et al ., 2013 ; Wang et al ., 2019 ). Fewer studies have examined changes in brain metabolism, which is an important marker for function. While clinical studies using [ 18 F]-fluoro-deoxyglucose (FDG) positron emission tomography (PET) typically examine patients in the chronic stage, often months to years after SCI, studies in rodent models of SCI are relatively few. Jaiswal et al. using [ 18 F]-FDG PET in rats have demonstrated a reduction in glucose uptake in the cerebellum 90 days after bilateral thoracic SCI ( Jaiswal et al ., 2022 ). Horner et al (1995) applied cerebral autoradiography to a rat model of bilateral thoracic SCI and analyzed a limited number of regions-of-interest 3 months after injury. They noted a reduction in glucose uptake in the ventral posterolateral thalamic nucleus (VPL), cerebellar lobules 7 and 8, and the nucleus gracilis ( Horner & Stokes, 1995 ). To our best knowledge, a whole-brain analysis of changes in glucose metabolism during the subacute phase of SCI has not been conducted. In the current study, we apply high-resolution, voxel-based, whole-brain autoradiographic mapping of glucose uptake 1 week after hemicontusive cervical SCI, at a time of functional brain reorganization before changes have become chronic. MATERIALS & METHODS Female C57/BL mice were purchased from Charles River (Hollister, CA, USA) at 8 - 10 weeks of age. Animals were housed on a 12-hour light/12-hour dark cycle (lights on from 7:00 am to 7:00 pm) in groups of four with direct bedding and with free access to water and standard rodent chow. All procedure and handling techniques were in strict accordance with the National Institutes of Health guidelines for the care and use of laboratory animals and approved by the Institutional Animal Care and Use Committee of the University of Southern California, with accreditation by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International. Studies were initiated after 1 week of acclimatization to the vivarium. Spinal cord surgical procedures The SCI model used in this study was a unilateral contusion injury model at the 5th cervical level (C5) as previously described ( Aguilar & Steward, 2010 ), with the change that the tip impactor was positioned on the right side of the cord, creating primarily unilateral deficits to the right forelimb ( Danilov et al ., 2020 ). Mice were deeply anesthetized through intraperitoneal injection of a cocktail of ketamine (100 mg/kg) and xylazine (10 mg/kg), and a dorsal laminectomy was performed on C5 ( n = 6). The contusion injury was created using the Infinite Horizon device platform (Precision Systems and Instrumentation, LLC, Fairfax Station, VA, USA). A moderate injury was achieved using an impactor (diameter = 1.3 mm) and an impact force of 80 kDyn.Control animals (Sham) were anesthetized and received skin incision only ( n = 7). Mice received a single dose of Ethiqa XR (3.25 mg/kg, s.c., MWI Animal Health, Concora Inc., Boise, ID, USA) prior to the surgery for analgesia, and a single dose of enrofloxacin (2.5 mg/kg, s.c., MWI Animal Health) post-surgery for prophylactic treatment against urinary tract infection. For 3 days post-surgery, mice received an injection of Ringer’s lactate solution daily (1 ml/20 g, s.c.) for hydration. Mice were housed individually following surgery. Behavioral evaluation SCI-induced motor deficits were assessed using the grip strength and accelerating rotarod test. In the grip strength test, a stainless-steel wire cage lid (wire diameter = 0.2 cm, inter-wire distance = 0.8 cm) was covered with duct tape around the edges to prevent the mouse from climbing around the rim, leaving a 6 cm x 10 cm window with exposed wires. On post-surgery day 6, the animal was tested in three trials with a 30-min inter-trail interval. In each trial, the mouse was placed on top of the lid where wires were exposed. The lid was slightly tilted to force the animal to grip the wires and then quickly turned upside down. The lid was held 40 cm from the floor, which was covered with 1-cm of bedding. The time-to-fall was recorded with a stopwatch manually with a 180-s cut-off time. The mean was calculated after removing the shortest time-to-fall. In the rotarod test, the animal was trained, and baseline measured over 3 days before the surgery. The animal was placed on the spindle (diameter = 7.3 cm) of the rotarod (Economex Rotarod, Columbus Instruments, Columbus, OH, USA) for 30 s followed by 5 min walking at 5 rpm (115 cm/min) for two days. On the 3 rd day, baseline was measured in 3 trials with a 30-min inter-trial interval. In each trial, the time-to-fall was recorded manually with a starting speed of 5 rpm, and an acceleration of 0.1 rpm/s (2.3 cm/min/s). The cut-off time was 300 s. The mean was calculated after removing the shortest time-to-fall. The animal was then tested on post-surgery day 6 and the mean was normalized to the baseline. Data were presented as mean ± standard error of mean for each group and analyzed using GraphPad Prism 10 (GraphPad Software, LLC., Boston, MA, USA). If the data passed the Shapiro-Wilk normality test, two-tailed Student’s t -test was used to evaluate between-group differences. Otherwise, two-tailed Mann-Whitney test was used. P < 0.05 was considered statistically significant. Measurement of cerebral glucose uptake at rest ( Holschneider et al ., 2019 ) On day 4 – 6 post-surgery, the mice were habituated to the experiment room with dim lighting for 15 min daily. On day 6, the mice were fasted overnight with free access to water. On day 7 post-surgery, each mouse was administered i.p. [ 14 C]-2-deoxyglucose (2DG, 0.3 µCi/g bodyweight in 0.53 ml saline, American Radiolabeled Chemicals, Inc., St. Louis, MO, USA), followed by a 45-min radiotracer uptake period in a resting state in home cage. Thereafter, mice were deeply anesthetized with 5% isoflurane and euthanized by cervical dislocation. Autoradiography Brains were extracted and flash frozen in methylbutane over dry ice (about - 55 ºC). Brains were then serially cryosectioned into coronal slices (20-μm thick, 140-μm inter-slice distance) at -18 ºC in a cryostat (Mikron HM550, Thermo Fisher Scientific, Waltham, MA, USA). Slices were heat-dried on glass slides and exposed to UltraCruz autoradiography film (Santa Cruz Biotechnology, Inc., Dallas, TX, USA) alongside [ 14 C] radioactivity standards (Amersham Biosciences, Piscataway, NJ, USA). Autoradiograms of brain slices were digitized on an 8-bit grey scale using a voltage-stabilized light box (Northern Light R95 Precision Illuminator, Imaging Research Inc., St. Catharines, Ontario, Canada) and a Retiga 4000R charge-coupled device monochrome camera (QImaging of Teledyne Photometrics, Tucson, AZ, USA). Regional cerebral glucose uptake (rCGU) was measured according to the method of Sokoloff ( Sokoloff et al ., 1977 ) with modification ( Melzer et al ., 1985 ; Jordan et al ., 2005 ; Vyazovskiy et al ., 2008 ). Spatial resolution of 2-DG autoradiographic imaging is ∼50 μm ( Stumpf & Solomon, 1995 ). Image Processing ( Nguyen et al ., 2004 ) 3-D brains were reconstructed from 70 consecutive autoradiograms (approximate bregma levels: + 1.54 mm to – 6.72 mm, voxel size: 40 μm x 140 μm x 40 μm) using TurboReg ( Thevenaz et al ., 1998 ) and a nonwarping geometric model (rotations, translations and nearest-neighbor interpolation). A brain template was created using our prior methods ( Thevenaz et al ., 1998 ), with background and ventricular spaces thresholded based on optical density. Spatial normalization consisted of a 12-parameter affine transformation followed by a nonlinear spatial normalization using 3-D discrete cosine transforms. Final normalized brains were smoothed with a Gaussian kernel (full-width at half-maximum = 240 μm × 420 μm × 240 μm) to improve the signal-to-noise ratio. To account for global differences in absolute amount of [ 14 C], voxel intensities of each brain were proportionally scaled. Analysis of regional cerebral glucose uptake (rCGU) and metabolic connectivity ( Holschneider et al ., 2019 ) Statistical parametric mapping ( Friston et al ., 1995 ; Nguyen et al ., 2004 ) (SPM5, Wellcome Centre for Neuroimaging, University College London, London, UK) was used for data analysis. Unbiased, voxel-by-voxel Student’s t -tests between the SCI and Sham group were performed across the whole brain to access changes in rCGU following SCI. Threshold for statistical significance was set at P < 0.05 at the voxel level with an extent threshold of 200 contiguous voxels, which reflects a balanced approach to control Type I and Type II errors. Regions were identified by a mouse brain atlas ( Franklin & Paxinos, 2007 ). We applied seed-ROI (region of interest) correlation analysis ( Holschneider et al ., 2014 ) to assess metabolic connectivity of the ventral posterolateral thalamic nucleus (VPL), a part of the sensory thalamus that receives monosynaptic input from the contralateral spinal cord. A circular, structural ROI was hand drawn in MRIcro (version 1.40, http://cnl.web.arizona.edu/mricro.htm ) in the left VPL at bregma – 1.58 mm over the template brain according the mouse brain atlas. Mean optical density of the seed ROI was extracted for each animal using the MarsBaR toolbox for SPM (version 0.42, http://marsbar.sourceforge.net/ ). Correlation analysis was performed in SPM for each group using the seed values as a covariate. Threshold for significance was set at P <0.05 at the voxel level and an extent threshold of 200 contiguous voxels. Regions showing significant correlations (positive or negative) in rCGU with the seed ROI are considered functionally connected with the seed. Immunohistochemistry Immunohistochemistry was performed as previously described ( Danilov & Steward, 2015 ). Mice were euthanized with an overdose of ketamine and xylazine (160 and 20 mg/kg bodyweight, respectively) and perfused transcardially with 4% paraformaldehyde in 0.1 M sodium phosphate buffer (Na 2 HPO 4 , pH 7.4). Spinal cords were dissected and post-fixed in 4% paraformaldehyde overnight, then immersed in 30% sucrose for cryoprotection overnight, frozen in TissueTek OCT (VWR International, Radnor, PA, USA) and stored at − 20°C until sectioning with a cryostat. The tissue block extending from ∼ 4 mm above to 4 mm below the lesion and containing the injury site was sectioned at 20 µm intervals in the horizontal plane. The sections were stained with specific antibodies for glial fibrillary acidic protein (GFAP Dako, Cat# Z0334). After blocking in 5% normal goat serum in PBS solution, sections were incubated in primary antibody (GFAP 1:1000) at 4 0 C overnight. The following day, sections were washed in PBS and incubated with the fluorescent secondary antibody (anti-rabbit Alexa Fluor 488, 1:250) for 2 hrs at RT. After twice rinsing in PBS, sections were mounted on gelatin subbed slides. Coverslips were applied with VECTASHIELD, Antifade Mounting Medium with DAPI (Cat # H-1200, Vector Laboratories, Burlingame, CA, USA). Images were obtained on a BZ-9000 (BIOREVO) fluorescence microscope (Keyence Corporation of America, Itasca, IL, USA). RESULTS Confirmation of unilateral lesion of the cervical spinal cord is shown in Fig. 1 . Immunohistochemical staining confirmed tissue loss in the right hemicord with superimposed image showing increases in GFAP immunostaining in the perilesional area. SCI compared to Sham animals demonstrated statistically significant deficits in the grip strength test (time-to-fall: SCI, 10.4 ± 8.0 s, n = 6; Sham, 171.8 ± 8.2 s, n = 7. P = 0.001, Mann-Whitney test) and the accelerating rotarod test (time-to-fall: SCI, 17.9 ± 7.0 %; Sham, 102.1 ± 5.7 % of baseline. P < 0.0001, Student’s t test), suggesting SCI-induced impairment in strength, coordination and balance ( Fig. 2 ). Download figure Open in new tab Fig. 1. Representative images of right unilateral lesion after an 80 kDyn contusive cervical spinal cord injury in mice Arrows indicate increased expression of glial fibrillary acidic protein (GFAP) in reactive astrocytes in response to injury. Download figure Open in new tab Fig. 2. Motor deficits after spinal cord injury (SCI). The spinal cord injury (SCI) mice showed statistically significant motor deficits compared to the Sham mice in the grip strength test (A, **: P = 0.001, Mann-Whitney test) and the accelerating rotarod test (B, ****: P < 0.0001, Student’s t test, n = 6 for SCI, 7 for Sham group). Statistically significant changes in rCGU were noted broadly in the SCI mice compared to Sham at rest 1 week following cervical hemicontusive SCI ( Table 1 , Fig. 3 ) . It is noteworthy that most of the SCI-related changes in rCGU were bilateral. SCI-related decreases in rCGU were seen mostly in the anterior part of the brain (rostral to ∼ bregma - 5.0 mm) including the primary and secondary somatosensory (S1, S2), primary and secondary motor (M1, M2), piriform (Pir), insular (I) cortices, basal ganglia (caudate putament CPu, globus pallidus GP, left substantia nigra SN, left subthalamic n. STh), thalamic nuclei (anterodorsal n. AD, habenula n. Hb, laterodorsal n. LD, mediodorsal n. MD, paraventricular n. PV, posterior n. Po, ventral posterolateral n. VPL; ventral posteromedial n. VPM), and left mesencephalic reticular formation (mRt). View this table: View inline View popup Table 1: Regions showing statistically significant differences in regional cerebral glucose uptake in mice at rest 1 week following cervical hemicontusive spinal cord injury compared to sham mice. Download figure Open in new tab Fig. 3. Effects of right, hemicontusive cervical spinal cord injury (SCI) on regional cerebral glucose uptake (rCGU) in the resting state 1 week following injury. Significant changes in rCGU in SCI mice compared to sham are shown. Representative coronal sections of the template brain (anterior-posterior level relative to the bregma shown in black textbox) depict the ipsilesional (right) and contralesional (left) hemispheres. The color-coded overlays are statistical parametric maps showing significant changes in rCGU (red/blue: increases/decreases, P 200 contiguous voxels, n = 6-7 per group). The bottom two images of the 3 rd column show significant changes near the surface of the 3-D rendered template brain. Abbreviations Acb, accumbens nucleus AD, anterodorsal thalamic n. Au, auditory cortex BL, basolateral amygdaloid n. BM, basomedial amygdaloid n. CA1/CA2/CA3, hippocampus CPu, striatum Crus1, crus of the ansiform lobule DG, dentate gyrus DLEnt, dorsolat.entorhinal cortex GP, external globus pallidus Hb, habenular n. I, insular cortex LD, lateral dorsal thalamic n. LDTg, laterodorsal tegmental n. LS, lateral septum M1/M2, primary/secondary motor cortex mcp, middle cerebellar peduncle MeA, medial amygdaloid n. PaS, parasubiculum Pir, piriform cortex PMCo, cortical amygdaloid n. Po, posterior n. thalamic n. PtA, parietal association cortex Rt, reticular thalamic n. S1/S2, primary/secondary somatosensory cortex SN, substantia nigra STh, subthalamic n. V2, secondary visual cortex Ve, vestibular n. VL, ventrolateral thalamic n. VM, ventromedial thalamic n. VP, ventral pallidum VPL, ventroposterior lateral thalamic n. VPM, ventroposterior medial thalamic n. ZI, zona incerta 4/5 Cb, lobules 4 & 5 of the vermis 5N, trigeminal motor n. In contrast, SCI-related increases in rCGU were noted in many limbic regions including the amygdala (basolateral n. BL, basomedial n. BM, medial n. anterior part MeA, posteromedial cortical n. PMCo), accumbens nucleus (shell AcbSh, right core AcbC), lateral septum (LS), posterior hypothalamus (PH), and hippocampus (CA1, CA2, CA3, dentate gyrus DG, parasubiculum PaS, dorsolateral entorhinal cortex DLEnt). Increases in rCGU were also seen in the cortex (posterior M2, S2, auditory Au, parietal association PtA, left primary/secondary visual V1/V2), cerebellum (lobules 4 and 5 of the vermis Cb4/5, interposed n. Int, lateral n. Lat, middle cerebellar peduncle mcp, crus 1 of the ansiform lobule Crus1), ventral pallidum (VP), thalamus (right anteromedial n. AM, right reticular n. Rt), and brainstem areas (parabrachial pigmented n. of the ventral tegmental area PBP, pontine reticular n. oral/caudal part PnO/PnC, right intermediate reticular n. IRt, laterodorsal tegmental n. LDTg, motor trigeminal n. 5N, vestibular n. Ve). The VPL is a major relay center for ascending input from the spinal cord and showed decreases in rCGU following SCI primarily on the contralesional side. We further applied seed correlation analysis to assess SCI-related changes in metabolic connectivity of the VPL. A seed representing the contralesional (left) VPL was selected at bregma -1.82 mm. Fig. 4 . compares metabolic connectivity of the VPL seed in the SCI and the Sham group. Compared to the Sham group, the SCI group showed greatly reduced positive metabolic connectivity with the motor (M1, M2), primary somatosensory (including forelimb S1FL, hindlimb S1HL, shoulder S1Sh, and barrel field S1BF areas), parietal association, and visual (V1/V2) cortices, as well as with the cerebellum (lobule 3 of the vermis 3Cb, simple lobule Sim, Crus1). The SCI group also showed negative correlation with the retrosplenial cortex (RS) and 3Cb, which were absent in the Sham group. There was also attenuation of intrathalamic connectivity in SCI compared to Sham mice (data not shown). Download figure Open in new tab Fig. 4. Changes in metabolic connectivity of the contralesional ventral posterolateral thalamic nucleus (VPL) to the cortex and cerebellum following hemicontusive cervical spinal cord injury (SCI). A seed representing the contralesional (left) VPL was selected at bregma -1.82 mm (inset on the left). The transverse view of the 3D rendered template brain is shown alongside three coronal sections the bregma levels of which are shown in the black textboxes and marked on the transverse figure with white horizontal lines (top panel: SCI; lower panel: Sham). Color-coded overlays show brain regions that have statistically significant correlations in regional cerebral glucose uptake with the VPL seed (red/blue: positive/negative correlation. P 200 contiguous voxels, n = 6-7 per group). For the 3D rendered images, visible depth of overlay was set to 1 mm to reveal cortical connectivity. Compared to the Sham group, the SCI group showed greatly reduced metabolic connectivity with motor and somatosensory cortices, a loss of positive correlation with the cerebellum, and newly emerged negative correlation with the retrosplenial and posterior visual cortices. Abbreviations: 3Cb (lobule 3 of the cerebellar vermis), Au (auditory cortex), Crus1 (crus 1 of the ansiform lobule), I (insular cortex), M1/M2 (primary/secondary motor cortex), PtA (parietal association cortex), RS (retrosplenial cortex), S1 (primary somatosensory cortex), S1BF (S1 barrel field), S1FL (S1 forelimb), S1HL (S1 hindlimb), S1Sh (S1 shoulder), Sim (simple lobule), V1/V2 (primary/secondary visual cortex). DISCUSSION Our results indicate extensive changes in regional cerebral glucose uptake in animals 1 week after hemicontusive cervical SCI compared to normal controls. Changes were associated with significant motor deficits on the grip strength test and accelerating rotarod test as previously reported ( Danilov et al ., 2020 ). Cerebral metabolic changes were regionally specific. In general (with exceptions as noted below), relative glucose uptake was decreased in forebrain motor sensory regions, as well as in regions of the basal ganglia and sensory thalamus. In contrast, regions in the limbic system and in the cerebellum demonstrated a relative increase in glucose uptake. A notable finding following the hemicontusive cervical SCI was the extent of bilateral changes in glucose metabolism. For example, hypometabolism was seen in the forelimb area of S1 in both the contralesional and ipsilesional hemisphere. Hemicontusive SCI at the cervical level has been shown to cause damage to both the gray and white matter (including the dorsal column, and to some extent the lateral and ventral funiculi). While a great majority of descending fibers, e.g. the corticospinal tract, originate in the contralateral hemisphere and cross the midline before reaching the spinal cord, different ascending fibers passing through the cervical segments target brain regions in both hemispheres. Fibers in the dorsal column cross the midline in the medulla and target the contralateral hemisphere. Other ascending fibers, e.g. spinothalamic tract, coming from the lower segments cross the midline below the cervical level and target the ipsilateral hemisphere. Damaged spinal neurons in the cervical segments can cause deafferentation of regions in the contralateral hemisphere. Therefore, hemicontusive cervical SCI can affect both hemisphere depending on the severity of lesion. Such profound reorganizations of the ipsilesional sensory-motor cortex after unilateral spinal cord injury has been previously reported in rats ( Ghosh et al ., 2009 ). Likewise, functional MRI (fMRI) in rodents has previously shown that while unilateral paw stimulation in normal animals results largely in activation of contralateral somatosensory cortex, in spinal cord-injured animals, there is a much more extensive activation, which includes contralateral but also ipsilateral structures such as cortex, thalamus, hippocampus, and the caudate putamen ( Ramu et al ., 2006 ). Such findings suggest functional reorganization and a broadening of the effects of injury to involve the ipsilesional hemisphere. Somatosensory Circuit In our data, somatosensory cortex (S1, S2) showed broad decreases in glucose uptake. These findings are consistent with prior neuroanatomical studies using both retrograde and anterograde tract tracing which demonstrated projection neurons from the cervical spinal cord to neurons throughout the forelimb area of the sensorimotor cortex and region of secondary somatosensory cortex (S2) ( Liang et al ., 2011 ; Steward et al ., 2021 ). Ghosh et al ( Ghosh et al ., 2009 ) using retrograde tracers injected after hemisection of the cervical spinal cord, found that corticospinal tract axons of the intact, nonlesioned side sprout across the midline of the spinal cord, with the ipsilesional sensory and motor cortices undergoing important reorganizations. More broadly, hypometabolism was observed in subcortical regions comprising the spinothalamic tract that processes somatosensory input from the limbs and trunk (ventral posterolateral thalamic nucleus), the face (ventroposteromedial thalamus), as well as pain and temperature (ventromedial posterior and mediodorsal nuclei of the thalamus). In addition, hypometabolism was noted in the posterior thalamic nucleus (Po) and the insula that play key roles in multimodal sensory integration and higher-order processing. These regions of the thalamus have been shown to bilaterally project to cervical regions of the spinal cord ( Burstein et al ., 1990 ). Altered electrophysiological responsiveness have previously been reported post-SCI in the PO, VPL and VPM in rats ( Gerke et al ., 2003 ; Paulson et al ., 2005 ; Hubscher & Johnson, 2006 ). In principle, the decreased glucose uptake we noted in these thalamic nuclei may be the result of deafferentation. Alternatively hypometabolism in the thalamus may be the result of activation of the ipsilateral reticular nucleus of the thalamus which provides inhibitory, GABAergic input to the dorsal thalamus, including the ventral posterior nuclei (VPL, VPM), lateral dorsal, posterior and ventral lateral nuclei and may have inhibited these structures ( Jones, 1975 ; Jones, 1985 ). In addition, the reticular nucleus is known to also inhibit neurons of the mesencephalic reticular formation which also showed decreased glucose uptake in our study ( Nanobashvili et al ., 2024 ). Of note, both major somatosensory tracts (the spinothalamic/anterolateral tract and the dorsal column-medial lemniscus pathway) from the right side of the spinal cord provide first order structural connections unilaterally to the left VPL. Given that the VPL receives a monosynaptic connection from the contralateral spinal cord, we examined the functional connectivity of the VPL in our dataset ( Fig. 5 ). Placement of a region-of-interest in the left (contralateral) VPL demonstrated significant functional correlation in SHAM animals within the extended region of the VPL, both on the left and right side. Though the left and right ventroposterolateral (VPL) nuclei do not share a structural connection through direct commissural fibers, others have in human subjects reported homotopic functional connectivity between bilateral VPL at rest and during motor tasks using fMRI ( Mancuso et al ., 2019 ; Charyasz et al ., 2025 ). This has been proposed to reflect indirect synchronization via corticothalamocortical loops and transcallosal exchanges between homologous somatosensory cortices rather than direct anatomical connections. In SCI animals, in contrast, functional connectivity within the VPL was significantly diminished. The VPL projects ipsilaterally to the primary somatosensory cortex (S1), with the oral subdivision of the VPL also sending thalamocortical axons to the ipsilateral primary motor cortex (M1). SCI animals in contrast to SHAM animals demonstrated a significant loss of functional connectivity to bilateral somatosensory cortex (S1, S1BF, S1FL, S1HL, S1ULp) and motor cortex (M1)(second order functional connections: Spinal cord→VPL→S1, M1), which themselves are known to have reciprocal monosynaptic structural connections to the VPL ( Horne & Tracey, 1979 ; Shook et al ., 1991 ; Clasca, 2023 ; Rubio-Teves et al ., 2024 ). This is consistent with prior work demonstrating using fMRI that functional connectivity between VPL and S1 is decreased 1 week after unilateral, cervical SCI, suggesting a disruption of second order synaptic connections ( Seminowicz et al ., 2012 ). Motor circuit Decreases in glucose uptake were noted in regions of the motor circuit, including primary motor cortex, striatum (dorsal, central, ventral), globus pallidus, subthalamic nucleus and the substantia nigra. Overall, the hypometabolism in motor cortex was less broadly represented than that in somatosensory cortex. Hypometabolism in the striatum was broadly seen in ventral regions, but in dorsal regions was significant mostly posteriorly. Prior work using anterograde and retrograde molecular tracers, as well as viral tract tracers has confirmed projections of the cervical spinal cord to motor cortex, striatum, globus pallidus and the subthalamic nucleus ( Newman et al ., 1996 ; Liang et al ., 2011 ; Kamiyama et al ., 2015 ; Poinsatte et al ., 2024 ). In contrast, a small significant increased glucose uptake was noted bilaterally in posterior secondary motor cortex, and in the contralateral ventrolateral (VL, motor) thalamus. Increases in activation of the contralateral VL assessed by perfusion changes have previously been reported by Morrow et al. after T12 to L3 spinal lesions ( Morrow et al ., 2000 ; Paulson et al ., 2005 ). Noteworthy, was that the cerebellum primarily showed bilateral increases in regional glucose uptake, including the lateral lobes (cruz1), lobules 4 and 5 of the vermis, the interposed and lateral deep cerebellar nuclei, as well as the middle cerebellar peduncle. The dorsal spinocerebellar tract projects mainly ipsilateral to the cerebellum, but a contralateral projection is also present ( Matsushita & Xiong, 1997 ). Prior work in clinical SCI patients using [ 18 F]-fluoro-2-deoxyglucose positron emission tomography ( 18 F-FDG PET) has also confirmed increased glucose uptake in the cerebellum ( Curt et al ., 2002b ; Chopra et al ., 2022 ), with changes also reported in cerebellar synaptic markers ( Visavadiya & Springer, 2016 ). Limbic circuit Different from somatosensory and motor regions, limbic areas after hemicontusive SCI prominently showed widespread increases in glucose uptake alongside select areas of hypometabolism. Increases were noted in the amygdala (basolateral n., medial n., cortical amygdala), nucleus accumbens (core, shell), lateral septum, hypothalamus (posterior), and hippocampus (CA1-3, DG). The functional changes in limbic regions are consistent with earlier studies showing that labelling of the amygdala and nucleus accumbens neurons with fluorogold showed retrograde uptake of the tracer throughout the spinal cord, in particular the upper cervical and lumbar segments ( Burstein & Giesler, 1989 ; Burstein & Potrebic, 1993 ). Anterograde and retrograde transport studies from the upper cervical spinal cord and the cervical enlargement have also demonstrated direct spinal projections to the amygdala, septum and hypothalamus ( Newman et al ., 1996 ; Liang et al ., 2011 ). Increased activation of the nucleus accumbens has been previously described as an important component of recovery after hemicontusion of the cervical spinal cord ( Sawada & Nishimura, 2021 ). In addition, our study showed decreases in glucose uptake in regions of the thalamus associated with processing of emotional information, including anterior midline structures (anterior, paraventricular), mediodorsal, habenular, as well as lateral dorsal nuclei. Prior evidence for structural or functional changes in limbic-related nuclei (mediodorsal, anterior, midline/intralaminar, lateral dorsal) after SCI is sparse. Metabolic imaging hints at widespread thalamic alterations, but targeted studies on emotional/limbic thalamic nuclei post-SCI remain an open area for research. Clinical correlates The occurrence of SCI sets into motion a set of neuronal, glial, neuroplastic, and inflammatory responses that take months to evolve. During this time, factors including the dying back of neurons, proliferation and activation of glial cells, compensatory and functional reorganization of neural circuits, shape regional cerebral metabolic needs. Changes in functional reorganization can occur as early as hours to days after injury ( Sydekum et al ., 2014 ; Yagüe et al ., 2014 ). During the transition from acute to chronic SCI, neural circuits may undergo changes in functional reorganization that differ across brain regions. For example, Jurkiewicz et al. reported that when SCI patients were imaged longitudinally during performance of a simple motor task shortly after injury and continuing over the course of 1 year, patients compared to healthy controls demonstrated increasing M1 activation, whereas associated sensorimotor areas showed a progressive decrease in activation ( Jurkiewicz et al ., 2007 ). In humans, most neuroimaging studies have focused on the chronic phase of SCI. Here, similar to our results, studies have reported a diffusion of functional activation (cerebral perfusion-based) to include the unaffected limb representation ( Curt et al ., 2002a ), as well as activation outside of the expected pattern of activation evoked by the particular motor task ( Bruehlmeier et al ., 1998 ). Increased activation of the cerebellum has also been reported in SCI patients during a motor challenge ( Bruehlmeier et al ., 1998 ; Curt et al ., 2002b ). 18 F-FDG-PET brain imaging in SCI patients has shown variable results. Some have reported reduced metabolic uptake in sensory cortical areas, anterior cingulate gyrus, and hippocampus ( Chopra et al ., 2022 ), others have reported such reductions in midbrain, the cerebellum and the temporal cortex ( Roelcke et al ., 1997 ). Raised metabolism has been reported in supplementary motor areas (SMA), inferior frontal gyrus, some areas in the parietal and temporal lobe, putamen and cerebellum ( Chopra et al ., 2022 ), or in SMA, anterior cingulate cortex and the putamen ( Roelcke et al ., 1997 ). Differences may relate to patient selection (paraplegia, tetraplegia), time since injury, as well as whether imaging was performed at rest or during a motor task. Functional brain reorganization after SCI has been implicated in a number of its debilitating sequelae. Reorganization of sensory circuits is proposed to contribute to hyperalgesia, while changes in limbic structures may contribute to depression, a frequent sequelae of SCI. Improved understanding of the interaction of the brain-spinal cord axis, as well as in structure-function relations may have important clinical implications for the evaluation and treatment of patients with SCI. Limitations Our study focused on the subacute phase (1 week) following SCI. We did not study longitudinal changes in neuroplasticity in remote brain networks. Understanding of the temporal course of brain changes may help in the future to define optimal timepoints for neurorehabilitative interventions. We did not examine brain functional activation during a motor or sensory challenge. Such challenges have the potential to unmask latent deficits not appreciated in the resting state. This may help explain the absence of metabolic changes in some regions that previously have been reported to demonstrate structural connections via tract tracing ( Liang et al ., 2011 ). Our findings of remote changes in cerebral glucose uptake after SCI does not directly address the mechanism of change, and whether this is induced by neuroinflammation, changes in glial cell activation ( Wu et al ., 2014a ; Wu et al ., 2014b ; von Leden et al ., 2016 ; Wu et al ., 2016 ), mitochondrial function ( Sullivan et al ., 2007 ; Wu et al ., 2020 ; Seira et al ., 2024 ), decreases in neuronal viability or a downregulation of glycolytic or aerobic pathways, or dysregulation of neural activity. Neither did we examine sex differences ( McFarlane et al ., 2020 ; Lee et al ., 2023 ; Mojarad et al ., 2025 ; Pacheco et al ., 2025 ) or strain differences ( Paulson et al ., 2005 ) which are beginning to be reported. Future work could consider direct examination of behavioral correlates, including sensory hyperalgesia, as well as allodynia-like hypersensitivity and their relationship to functional brain changes. Funding The authors have not disclosed any funding. Data statement Data access requests should be sent to the corresponding author and will be granted with the signing of a data sharing agreement. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgements REFERENCES ↵ Aguilar , R.M. & Steward , O. ( 2010 ) A bilateral cervical contusion injury model in mice: assessment of gripping strength as a measure of forelimb motor function . Exp Neurol , 221 , 38 – 53 . OpenUrl CrossRef PubMed ↵ Bruehlmeier , M. , Dietz , V. , Leenders , K.L. , Roelcke , U. , Missimer , J. & Curt , A. ( 1998 ) How does the human brain deal with a spinal cord injury? Eur J Neurosci , 10 , 3918 – 3922 . OpenUrl CrossRef PubMed Web of Science ↵ Burstein , R. , Dado , R.J. & Giesler , G.J. , Jr . . ( 1990 ) The cells of origin of the spinothalamic tract of the rat: a quantitative reexamination . Brain Res , 511 , 329 – 337 . OpenUrl CrossRef PubMed Web of Science ↵ Burstein , R. & Giesler , G.J. , Jr . . ( 1989 ) Retrograde labeling of neurons in spinal cord that project directly to nucleus accumbens or the septal nuclei in the rat . Brain Res , 497 , 149 – 154 . OpenUrl CrossRef PubMed Web of Science ↵ Burstein , R. & Potrebic , S. ( 1993 ) Retrograde labeling of neurons in the spinal cord that project directly to the amygdala or the orbital cortex in the rat . J Comp Neurol , 335 , 469 – 485 . OpenUrl CrossRef PubMed Web of Science ↵ Calderone , A. , Cardile , D. , De Luca , R. , Quartarone , A. , Corallo , F. & Calabrò , R.S. ( 2024 ) Brain Plasticity in Patients with Spinal Cord Injuries: A Systematic Review . Int J Mol Sci , 25 . ↵ Charyasz , E. , Erb , M. , Bause , J. , Heule , R. , Bender , B. , Jangir , V.K. , Grodd , W. & Scheffler , K. ( 2025 ) Functional connectivity of thalamic nuclei during sensorimotor task-based fMRI at 9.4 Tesla . Front Neurosci , 19 , 1568222 . OpenUrl PubMed ↵ Chopra , J. , D’Souza M M. , Jaimini , A. , Sharma , R. , Saw , S. , Pandey , S. & Solanki , Y. ( 2022 ) 18F-FDG 18F-FDG Positron Emission Tomography Imaging of Cortical Reorganization in Spinal Trauma . Indian J Nucl Med , 37 , 126 – 132 . OpenUrl PubMed ↵ Clasca , F. , Hofer , S.B. , Usrey , W.M. , Sherman , S.M. Clasca , F. ( 2023 ) Thalamic Output Pathways: Global Layout and Nucleus-Level Organization . In Clasca , F. , Hofer , S.B. , Usrey , W.M. , Sherman , S.M. (eds) The Cerebral Cortex and Thalamus . Oxford University Press , pp. 109 – 120 . ↵ Curt , A. , Alkadhi , H. , Crelier , G.R. , Boendermaker , S.H. , Hepp-Reymond , M.C. & Kollias , S.S. ( 2002a ) Changes of non-affected upper limb cortical representation in paraplegic patients as assessed by fMRI . Brain , 125 , 2567 – 2578 . OpenUrl CrossRef PubMed Web of Science ↵ Curt , A. , Bruehlmeier , M. , Leenders , K.L. , Roelcke , U. & Dietz , V. ( 2002b ) Differential effect of spinal cord injury and functional impairment on human brain activation . J Neurotrauma , 19 , 43 – 51 . OpenUrl CrossRef PubMed Web of Science ↵ Danilov , C.A. , Gu , Y. , Punj , V. , Wu , Z. , Steward , O. , Schönthal , A.H. , Tahara , S.M. , Hofman , F.M. & Chen , T.C. ( 2020 ) Intravenous delivery of microRNA-133b along with Argonaute-2 enhances spinal cord recovery following cervical contusion in mice . Spine J , 20 , 1138 – 1151 . OpenUrl PubMed ↵ Danilov , C.A. & Steward , O. ( 2015 ) Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice . Exp Neurol , 266 , 147 – 160 . OpenUrl CrossRef PubMed ↵ Filli , L. & Schwab , M.E. ( 2015 ) Structural and functional reorganization of propriospinal connections promotes functional recovery after spinal cord injury . Neural Regen Res , 10 , 509 – 513 . OpenUrl PubMed ↵ Fouad , K. , Pedersen , V. , Schwab , M.E. & Brösamle , C. ( 2001 ) Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses . Curr Biol , 11 , 1766 – 1770 . OpenUrl CrossRef PubMed Web of Science ↵ Franklin , K.B.J. & Paxinos , G. ( 2007 ) The Mouse Brain in Stereotactic Coordinates . Academic Press , San Diego, CA . ↵ Friston , K.J. , Holmes , A. , Worsley , K.J. , Poline , J.B. , Frith , C.D. & Frackowiak , R.S. ( 1995 ) Statistical parametric maps in functional imaging: A general linear approach . Human Brain Mapping , 2 , 189 – 210 . OpenUrl CrossRef ↵ Gerke , M.B. , Duggan , A.W. , Xu , L. & Siddall , P.J. ( 2003 ) Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury . Neuroscience , 117 , 715 – 722 . OpenUrl CrossRef PubMed Web of Science ↵ Ghosh , A. , Sydekum , E. , Haiss , F. , Peduzzi , S. , Zörner , B. , Schneider , R. , Baltes , C. , Rudin , M. , Weber , B. & Schwab , M.E. ( 2009 ) Functional and anatomical reorganization of the sensory-motor cortex after incomplete spinal cord injury in adult rats . J Neurosci , 29 , 12210 – 12219 . OpenUrl Abstract / FREE Full Text ↵ Harvey , P.J. , Li , Y. , Li , X. & Bennett , D.J. ( 2006 ) Persistent sodium currents and repetitive firing in motoneurons of the sacrocaudal spinal cord of adult rats . J Neurophysiol , 96 , 1141 – 1157 . OpenUrl CrossRef PubMed Web of Science ↵ Holschneider , D.P. , Guo , Y. , Wang , Z. , Vidal , M. & Scremin , O.U. ( 2019 ) Positive Allosteric Modulation of Cholinergic Receptors Improves Spatial Learning after Cortical Contusion Injury in Mice . J Neurotrauma , 36 , 2233 – 2245 . OpenUrl CrossRef PubMed ↵ Holschneider , D.P. , Wang , Z. & Pang , R.D. ( 2014 ) Functional connectivity-based parcellation and connectome of cortical midline structures in the mouse: a perfusion autoradiography study . Front Neuroinform , 8 , 61 . OpenUrl PubMed ↵ Horne , M.K. & Tracey , D.J. ( 1979 ) The afferents and projections of the ventroposterolateral thalamus in the monkey . Exp Brain Res , 36 , 129 – 141 . OpenUrl CrossRef PubMed Web of Science ↵ Horner , P.J. & Stokes , B.T. ( 1995 ) Fetal transplantation following spinal contusion injury results in chronic alterations in CNS glucose metabolism . Exp Neurol , 133 , 231 – 243 . OpenUrl PubMed ↵ Hubscher , C.H. & Johnson , R.D. ( 2006 ) Chronic spinal cord injury induced changes in the responses of thalamic neurons . Exp Neurol , 197 , 177 – 188 . OpenUrl CrossRef PubMed Web of Science ↵ Jain , N. , Florence , S.L. , Qi , H.X. & Kaas , J.H. ( 2000 ) Growth of new brainstem connections in adult monkeys with massive sensory loss . Proc Natl Acad Sci U S A , 97 , 5546 – 5550 . OpenUrl Abstract / FREE Full Text ↵ Jaiswal , S. , Brabazon , F. , von Leden , R. , Acs , D. , Collier , S. , Allison , N. , Dardzinski , B. & Byrnes , K.R. ( 2022 ) Spinal cord injury chronically depresses glucose uptake in the rodent model . Neurosci Lett , 771 , 136416 . OpenUrl PubMed ↵ Jones , E.G. ( 1975 ) Some aspects of the organization of the thalamic reticular complex . J Comp Neurol , 162 , 285 – 308 . OpenUrl CrossRef PubMed Web of Science ↵ Jones , E.G. ( 1985 ) The Thalamus . Springer , New York, N.Y . ↵ Jordan , G.R. , McCulloch , J. , Shahid , M. , Hill , D.R. , Henry , B. & Horsburgh , K. ( 2005 ) Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography . Neuropharmacology , 49 , 254 – 264 . OpenUrl CrossRef PubMed ↵ Jurkiewicz , M.T. , Mikulis , D.J. , McIlroy , W.E. , Fehlings , M.G. & Verrier , M.C. ( 2007 ) Sensorimotor cortical plasticity during recovery following spinal cord injury: a longitudinal fMRI study . Neurorehabil Neural Repair , 21 , 527 – 538 . OpenUrl CrossRef PubMed Web of Science ↵ Kamiyama , T. , Kameda , H. , Murabe , N. , Fukuda , S. , Yoshioka , N. , Mizukami , H. , Ozawa , K. & Sakurai , M. ( 2015 ) Corticospinal tract development and spinal cord innervation differ between cervical and lumbar targets . J Neurosci , 35 , 1181 – 1191 . OpenUrl Abstract / FREE Full Text ↵ Kim , B.G. , Dai , H.N. , McAtee , M. , Vicini , S. & Bregman , B.S. ( 2006 ) Remodeling of synaptic structures in the motor cortex following spinal cord injury . Exp Neurol , 198 , 401 – 415 . OpenUrl CrossRef PubMed Web of Science ↵ Lee , S.E. , Greenough , E.K. , Oancea , P. , Scheinfeld , A.R. , Douglas , A.M. & Gaudet , A.D. ( 2023 ) Sex Differences in Pain: Spinal Cord Injury in Female and Male Mice Elicits Behaviors Related to Neuropathic Pain . J Neurotrauma , 40 , 833 – 844 . OpenUrl CrossRef PubMed ↵ Li , G.L. , Farooque , M. , Isaksson , J. & Olsson , Y. ( 2004 ) Changes in synapses and axons demonstrated by synaptophysin immunohistochemistry following spinal cord compression trauma in the rat and mouse . Biomed Environ Sci , 17 , 281 – 290 . OpenUrl PubMed ↵ Liang , H. , Paxinos , G. & Watson , C. ( 2011 ) Projections from the brain to the spinal cord in the mouse . Brain Struct Funct , 215 , 159 – 186 . OpenUrl CrossRef PubMed Web of Science ↵ Mancuso , L. , Costa , T. , Nani , A. , Manuello , J. , Liloia , D. , Gelmini , G. , Panero , M. , Duca , S. & Cauda , F. ( 2019 ) The homotopic connectivity of the functional brain: a meta-analytic approach . Sci Rep , 9 , 3346 . OpenUrl PubMed ↵ Matsushita , M. & Xiong , G. ( 1997 ) Projections from the cervical enlargement to the cerebellar nuclei in the rat, studied by anterograde axonal tracing . J Comp Neurol , 377 , 251 – 261 . OpenUrl CrossRef PubMed ↵ McFarlane , K. , Otto , T.E. , Bailey , W.M. , Veldhorst , A.K. , Donahue , R.R. , Taylor , B.K. & Gensel , J.C. ( 2020 ) Effect of Sex on Motor Function, Lesion Size, and Neuropathic Pain after Contusion Spinal Cord Injury in Mice . J Neurotrauma , 37 , 1983 – 1990 . OpenUrl CrossRef PubMed ↵ Melzer , P. , Van der Loos , H. , Dorfl , J. , Welker , E. , Robert , P. , Emery , D. & Berrini , J.C. ( 1985 ) A magnetic device to stimulate selected whiskers of freely moving or restrained small rodents: its application in a deoxyglucose study . Brain Res , 348 , 229 – 240 . OpenUrl CrossRef PubMed Web of Science ↵ Mojarad , N. , Doyle , D. , Garmo , L.G. , Graff , R. , Reed , K. , Wolbert , P.A. , Uprety , A. , Stewart , B. , Rossignol , J. & Dunbar , G.L. ( 2025 ) Sex and Strain-Specific Variations in Motor Recovery Following Compression Spinal Cord Injury: Comparison of Sprague-Dawley and Wistar Rats . Brain Sci , 15 . ↵ Morrow , T.J. , Paulson , P.E. , Brewer , K.L. , Yezierski , R.P. & Casey , K.L. ( 2000 ) Chronic, selective forebrain responses to excitotoxic dorsal horn injury . Exp Neurol , 161 , 220 – 226 . OpenUrl CrossRef PubMed Web of Science ↵ Murray , K.C. , Nakae , A. , Stephens , M.J. , Rank , M. , D’Amico , J. , Harvey , P.J. , Li , X. , Harris , R.L. , Ballou , E.W. , Anelli , R. , Heckman , C.J. , Mashimo , T. , Vavrek , R. , Sanelli , L. , Gorassini , M.A. , Bennett , D.J. & Fouad , K. ( 2010 ) Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors . Nat Med , 16 , 694 – 700 . OpenUrl CrossRef PubMed Web of Science ↵ Nanobashvili , Z.I. , Bilanishvili , I.G. , Buachidze , B.B. , Barbakadze , M.D. & Khizanishvili , N.A. ( 2024 ) Interaction between the Reticular Nucleus of the Thalamus and Different Brainstem Structures New Visins in Medicine and Medical Science , pp. 160 – 172 . ↵ Nardone , R. , Holler , Y. , Brigo , F. , Seidl , M. , Christova , M. , Bergmann , J. , Golaszewski , S. & Trinka , E. ( 2013 ) Functional brain reorganization after spinal cord injury: systematic review of animal and human studies . Brain Res , 1504 , 58 – 73 . OpenUrl CrossRef PubMed ↵ Newman , H.M. , Stevens , R.T. & Apkarian , A.V. ( 1996 ) Direct spinal projections to limbic and striatal areas: anterograde transport studies from the upper cervical spinal cord and the cervical enlargement in squirrel monkey and rat . J Comp Neurol , 365 , 640 – 658 . OpenUrl CrossRef PubMed Web of Science ↵ Nguyen , P.T. , Holschneider , D.P. , Maarek , J.M. , Yang , J. & Mandelkern , M.A. ( 2004 ) Statistical parametric mapping applied to an autoradiographic study of cerebral activation during treadmill walking in rats . Neuroimage , 23 , 252 – 259 . OpenUrl CrossRef PubMed Web of Science ↵ Oudega , M. & Perez , M.A. ( 2012 ) Corticospinal reorganization after spinal cord injury . J Physiol , 590 , 3647 – 3663 . OpenUrl CrossRef PubMed ↵ Pacheco , M.R. , Tran , A.V. , Bradley , M.L. , Leal-Garcia , M.E. , Ozturgut , M. , Barnett , E.A. , Chakka , V.V. , Devaraj , S. , Kirchhoff , M. , Mulamba , T. , Thomas , K. , Vu , N.V. & McCreedy , D.A. ( 2025 ) Mature neutrophils promote long-term functional recovery after spinal cord injury in a sex-dependent manner . bioRxiv . ↵ Paulson , P.E. , Gorman , A.L. , Yezierski , R.P. , Casey , K.L. & Morrow , T.J. ( 2005 ) Differences in forebrain activation in two strains of rat at rest and after spinal cord injury . Exp Neurol , 196 , 413 – 421 . OpenUrl CrossRef PubMed ↵ Poinsatte , K. , Kenwood , M. , Betz , D. , Nawaby , A. , Ajay , A.D. , Xu , W. , Plautz , E.J. , Kong , X. , Ramirez , D.M.O. & Goldberg , M.P. ( 2024 ) SpinalTRAQ: A novel volumetric cervical spinal cord atlas identifies the corticospinal tract synaptic projectome in healthy and post-stroke mice . bioRxiv . ↵ Ramu , J. , Bockhorst , K.H. , Mogatadakala , K.V. & Narayana , P.A. ( 2006 ) Functional magnetic resonance imaging in rodents: Methodology and application to spinal cord injury . J Neurosci Res , 84 , 1235 – 1244 . OpenUrl PubMed ↵ Roelcke , U. , Curt , A. , Otte , A. , Missimer , J. , Maguire , R.P. , Dietz , V. & Leenders , K.L. ( 1997 ) Influence of spinal cord injury on cerebral sensorimotor systems: a PET study . J Neurol Neurosurg Psychiatry , 62 , 61 – 65 . OpenUrl Abstract / FREE Full Text ↵ Rubio-Teves , M. , Martín-Correa , P. , Alonso-Martínez , C. , Casas-Torremocha , D. , García-Amado , M. , Timonidis , N. , Sheiban , F.J. , Bakker , R. , Tiesinga , P. , Porrero , C. & Clascá , F. ( 2024 ) Beyond Barrels: Diverse Thalamocortical Projection Motifs in the Mouse Ventral Posterior Complex . The Journal of Neuroscience , 44 , e1096242024 . OpenUrl Abstract / FREE Full Text ↵ Sawada , M. & Nishimura , Y. ( 2021 ) Role of the nucleus accumbens in functional recovery from spinal cord injury . Neurosci Res , 172 , 1 – 6 . OpenUrl PubMed ↵ Seira , O. , Park , H.D. , Liu , J. , Poovathukaran , M. , Clarke , K. , Boushel , R. & Tetzlaff , W. ( 2024 ) Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course . Cells , 13 . ↵ Seminowicz , D.A. , Jiang , L. , Ji , Y. , Xu , S. , Gullapalli , R.P. & Masri , R. ( 2012 ) Thalamocortical asynchrony in conditions of spinal cord injury pain in rats . J Neurosci , 32 , 15843 – 15848 . OpenUrl Abstract / FREE Full Text ↵ Shook , B.L. , Schlag-Rey , M. & Schlag , J. ( 1991 ) Primate supplementary eye field. II. Comparative aspects of connections with the thalamus, corpus striatum, and related forebrain nuclei . J Comp Neurol , 307 , 562 – 583 . OpenUrl CrossRef PubMed Web of Science ↵ Sokoloff , L. , Reivich , M. , Kennedy , C. , Des Rosiers , M.H. , Patlak , C.S. , Pettigrew , K.D. , Sakurada , O. & Shinohara , M. ( 1977 ) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat . J Neurochem , 28 , 897 – 916 . OpenUrl CrossRef PubMed Web of Science ↵ Solstrand Dahlberg , L. , Becerra , L. , Borsook , D. & Linnman , C. ( 2018 ) Brain changes after spinal cord injury, a quantitative meta-analysis and review . Neurosci Biobehav Rev , 90 , 272 – 293 . OpenUrl CrossRef PubMed ↵ Steward , O. , Yee , K.M. , Metcalfe , M. , Willenberg , R. , Luo , J. , Azevedo , R. , Martin-Thompson , J.H. & Gandhi , S.P. ( 2021 ) Rostro-Caudal Specificity of Corticospinal Tract Projections in Mice . Cereb Cortex , 31 , 2322 – 2344 . OpenUrl CrossRef PubMed ↵ Stumpf , W.E. & Solomon , H.F. ( 1995 ) Autoradiography and Correlative Imaging . Academic Press , New York . ↵ Sullivan , P.G. , Krishnamurthy , S. , Patel , S.P. , Pandya , J.D. & Rabchevsky , A.G. ( 2007 ) Temporal characterization of mitochondrial bioenergetics after spinal cord injury . J Neurotrauma , 24 , 991 – 999 . OpenUrl CrossRef PubMed Web of Science ↵ Sydekum , E. , Ghosh , A. , Gullo , M. , Baltes , C. , Schwab , M. & Rudin , M. ( 2014 ) Rapid functional reorganization of the forelimb cortical representation after thoracic spinal cord injury in adult rats . Neuroimage , 87 , 72 – 79 . OpenUrl CrossRef PubMed ↵ Takeoka , A. , Vollenweider , I. , Courtine , G. & Arber , S. ( 2014 ) Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury . Cell , 159 , 1626 – 1639 . OpenUrl CrossRef PubMed ↵ Thevenaz , P. , Ruttimann , U.E. & Unser , M. ( 1998 ) A pyramid approach to subpixel registration based on intensity . IEEE Trans. Image Process , 7 , 27 – 41 . OpenUrl CrossRef PubMed Web of Science ↵ Vavrek , R. , Girgis , J. , Tetzlaff , W. , Hiebert , G.W. & Fouad , K. ( 2006 ) BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal cord injured rats . Brain , 129 , 1534 – 1545 . OpenUrl CrossRef PubMed Web of Science ↵ Visavadiya , N.P. & Springer , J.E. ( 2016 ) Altered Cerebellar Circuitry following Thoracic Spinal Cord Injury in Adult Rats . Neural Plast , 2016 , 8181393 . OpenUrl PubMed ↵ von Leden , R.E. , Selwyn , R.G. , Jaiswal , S. , Wilson , C.M. , Khayrullina , G. & Byrnes , K.R. ( 2016 ) (18)F-FDG-PET imaging of rat spinal cord demonstrates altered glucose uptake acutely after contusion injury . Neurosci Lett , 621 , 126 – 132 . OpenUrl CrossRef PubMed ↵ Vyazovskiy , V.V. , Cirelli , C. , Tononi , G. & Tobler , I. ( 2008 ) Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice . Brain Res Bull , 75 , 591 – 597 . OpenUrl CrossRef PubMed Web of Science ↵ Wang , W. , Xie , W. , Zhang , Q. , Liu , L. , Liu , J. , Zhou , S. , Shi , J. , Chen , J. & Ning , B. ( 2019 ) Reorganization of the brain in spinal cord injury: a meta-analysis of functional MRI studies . Neuroradiology , 61 , 1309 – 1318 . OpenUrl CrossRef PubMed ↵ Weidner , N. , Ner , A. , Salimi , N. & Tuszynski , M.H. ( 2001 ) Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury . Proc Natl Acad Sci U S A , 98 , 3513 – 3518 . OpenUrl Abstract / FREE Full Text ↵ Wu , J. , Stoica , B.A. , Luo , T. , Sabirzhanov , B. , Zhao , Z. , Guanciale , K. , Nayar , S.K. , Foss , C.A. , Pomper , M.G. & Faden , A.I. ( 2014a ) Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment. Involvement of cell cycle activation . Cell Cycle , 13 , 2446 – 2458 . OpenUrl PubMed ↵ Wu , J. , Zhao , Z. , Kumar , A. , Lipinski , M.M. , Loane , D.J. , Stoica , B.A. & Faden , A.I. ( 2016 ) Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury . J Neurotrauma , 33 , 1919 – 1935 . OpenUrl CrossRef PubMed ↵ Wu , J. , Zhao , Z. , Sabirzhanov , B. , Stoica , B.A. , Kumar , A. , Luo , T. , Skovira , J. & Faden , A.I. ( 2014b ) Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways . J Neurosci , 34 , 10989 – 11006 . OpenUrl Abstract / FREE Full Text ↵ Wu , L. , Niu , Z. , Hu , X. , Liu , H. , Li , S. , Chen , L. , Zheng , D. , Liu , Z. , Liu , T. , Xu , F. , Manyande , A. , Wang , J. & Xia , H. ( 2020 ) Regional cerebral metabolic levels and turnover in awake rats after acute or chronic spinal cord injury . Faseb j , 34 , 10547 – 10559 . OpenUrl PubMed ↵ Yagüe , J.G. , Humanes-Valera , D. , Aguilar , J. & Foffani , G. ( 2014 ) Functional reorganization of the forepaw cortical representation immediately after thoracic spinal cord hemisection in rats . Exp Neurol , 257 , 19 – 24 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted October 02, 2025. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Changes in cerebral glucose metabolism at rest following hemicontusive spinal cord injury in mice: A whole-brain autoradiographic study Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. 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