Sex differences in latent inhibition and their implications for psychotic disorders

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Mawson , View ORCID Profile Jeremy Hall , View ORCID Profile Kerrie L. Thomas doi: https://doi.org/10.1101/2025.09.24.677991 Eleanor R. Mawson a Cardiff University Neuroscience and Mental Health Innovation Institute. Hadyn Ellis Building , Maindy Road, Cardiff, United Kingdom , CF24 4HQ b Division of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine. Hadyn Ellis Building , Maindy Road, Cardiff, CF24 4HQ c Cardiff University Centre for Neuropsychiatric Genetics and Genomics. Hadyn Ellis Building , Maindy Road, Cardiff, United Kingdom , CF24 4HQ Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eleanor R. Mawson For correspondence: mawsoner{at}cardiff.ac.uk hallj10{at}cardiff.ac.uk thomaskl5{at}cardiff.ac.uk Jeremy Hall a Cardiff University Neuroscience and Mental Health Innovation Institute. Hadyn Ellis Building , Maindy Road, Cardiff, United Kingdom , CF24 4HQ b Division of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine. Hadyn Ellis Building , Maindy Road, Cardiff, CF24 4HQ Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jeremy Hall Kerrie L. Thomas a Cardiff University Neuroscience and Mental Health Innovation Institute. Hadyn Ellis Building , Maindy Road, Cardiff, United Kingdom , CF24 4HQ b Division of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine. Hadyn Ellis Building , Maindy Road, Cardiff, CF24 4HQ Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kerrie L. Thomas Abstract Full Text Info/History Metrics Preview PDF Abstract Latent inhibition (LI) has been extensively studied to investigate associative learning and memory processes as well as modelling aberrant attribution of salience to irrelevant stimuli in both humans and animals, a process which is thought to underpin hallucinations and delusions in psychosis. Despite sex differences observed in numerous aspects of psychosis, few studies have attempted to characterise sex differences in LI. This systematic review outlines the current evidence of sex differences in LI in both human and rodent studies, showing predominantly inconclusive and conflicting evidence for sex differences. We present data demonstrating sex differences in latent inhibition of contextual fear conditioning and associated gene expression in the hippocampus in rodents, supporting sex differences in latent inhibition at the behavioural and neurobiological levels. The systematic review suggests that although there have been relatively few studies of sex differences in LI, the data suggest that in hippocampally dependent forms of LI, sex differences may be more apparent, which may be of relevance in relation to sex differences in the presentation of psychosis. 1. Introduction Associative learning is one means through which humans and other animals utilise knowledge of prior experiences that have co-occurred with a stimulus or environment to predict future outcomes and direct behaviour. Latent inhibition (LI) refers to the reduced behavioural expression of associative learning and memory produced by the pairing of a conditioned stimulus (CS), or context (i.e., the environment in which learning takes place), with an unconditioned stimulus (US) when the subject has been previously exposed to the CS, or context, alone without any reinforcement ( Lubow, 1973 ). LI is observed in both humans and animals, and the majority of both rodent and human conditioning experiments have paired a discrete CS with a US, a paradigm known as cued conditioning ( Curzon et al., 2009 ). Cued conditioning involves an element of contextual learning, and cued LI has been shown to be context-dependent ( Miller et al., 2015 ). However, contextual fear conditioning (CFC) differs from cued conditioning protocols, in that the US is not paired with a discrete neutral stimulus, but rather only to an environment, or context. Latent inhibition experiments employing CFC protocols involve pre-exposing the individual to the context prior to conditioning ( Curzon et al., 2009 ). Deficits in LI have been implicated in psychosis ( Weiner, 2003 ), and there are numerous sex differences in the clinical presentation of psychosis ( Li et al., 2016 ). Hence, when investigating the role of LI or any cognitive mechanism implicated in psychosis, it is important to determine whether the cognitive process or its underlying mechanisms may differ between sexes and thus may explain the observed sex differences in clinical features. When developing novel precision treatments that target underlying biology, if this biology differs between sexes, treatment efficacy may be unequitable between sexes. Despite the extensive body of research on LI, most studies have not included sex as a factor in their analysis and behavioural neuroscience studies have been historically biased towards the sole inclusion of male animals. Hence, any inferences relating to learning and memory function may be erroneously extrapolated to females without evidence that such processes occur in the same manner in both sexes. This review aims to outline our current understanding of the sex differences in LI by conducting a systematic review of the literature in both rodents and humans across both cued and contextual associative learning paradigms. Furthermore, novel data are presented relating to sex differences in the LI of contextual fear conditioning. Additionally, the relationship between LI and psychosis will be explored, and how characterising sex differences in LI can be used to improve our understanding of sexually dimorphic psychopathologies such as schizophrenia and bipolar disorder will be discussed. 2. Mechanisms underpinning Latent Inhibition Several theories have attempted to explain the phenomenon of LI whereby nonreinforced preexposure of a CS results in impaired subsequent CS-US associations. Attentional theories such as the Conditioned Attention Theory ( Braunstein-Bercovitz and Lubow, 1998 ; Lubow, 1989 ) posit that LI functions as an adaptive mechanism to direct limited attentional resources to stimuli that best predict relevant outcomes, thereby conserving cognitive resources for novel or predictive stimuli. Conversely, associative theories such as the switching model of LI assert that LI occurs as a result of competing associations of CS-no US formed during pre-exposure and CS-US acquired during conditioning, rather than diminishing attention to the CS ( Bouton, 1993 ; Escobar et al., 2002 ; Hall and Rodriguez, 2010 ; Weiner, 2003 ). Converging evidence from lesion, pharmacological, and optogenetic studies has implicated a distributed neural circuit in LI, including the ventral tegmental area (VTA), nucleus accumbens (NAc), medial pre-frontal cortex (mPFC), and hippocampus. Amphetamine administration as well as more recent optogenetic experiments have revealed that dopaminergic input from the VTA to the NAc plays a key role in latent inhibition ( Gray et al., 1997 ; Kutlu et al., 2022 ; Weiner and Feldon, 1997 ). Bidirectional dopaminergic circuitry between the VTA and hippocampus is also thought to encode novel information into long-term memory, and part of this network includes the entorhinal cortex (ENT) ( Lisman and Grace, 2005 ). Control of dopaminergic transmission to the NAc has also been shown to be exerted by the ENT ( Jeanblanc et al., 2004 ). Evidence in support of the role of the mPFC in latent inhibition has been mixed, with some showing mPFC pharmacological lesioning to disrupt LI ( Lingawi et al., 2016 ), and others showing no effect ( Lacroix et al., 2000 , 1998 ). However, mPFC substructure specificity has been shown, with lesioning to prelimbic (PL) but not the infralimbic (IL) mPFC ( Nelson et al., 2010 ), and ventral but not dorsal mPFC ( George et al., 2010 ) altering LI response. The hippocampus is integral to the formation of cognitive representations of contexts, whereby individual components of the environment are consolidated into a singular stable representation ( Rudy, 2009 ; Smith and Bulkin, 2014 ), and is hence a critical structure in the formation of contextual fear memories and subsequent associations ( Anagnostaras et al., 2001 ). Context is important for LI as LI is abolished when pre-exposure and subsequent conditioning or testing occur in different contexts ( Escobar et al., 2002 ; Westbrook et al., 2000 ), and the hippocampus has been shown to be crucial to this specificity ( Honey and Good, 1993 ). Alongside the hippocampus, the IL and PL regions of the mPFC appear to play competing roles in regulating the context specificity of LI. The importance of the mPFC to has been shown through the use of functional inactivation experiments, in which lesioning specifically to the IL blocks LI, indicating a general function for the IL in the storage and retrieval of CS-no US of context-no US memory ( Lingawi et al., 2016 ; Piantadosi and Floresco, 2014 ). However, more recent studies suggest a more nuanced role for mPFC regions, with the PL and IL modulating the context specificity of first and second learned associations such that lesions of the PL or IL can inhibit or enhance LI respectively ( George et al., 2023 , 2010 ). Alterations in dopaminergic signalling in the striatum and PFC, alongside altered transmission of glutamate and GABA, have been implicated in the neurobiology underpinning psychosis ( Howes et al., 2024 ), and studying the role of dopamine in cognitive processes thought to relate to psychosis, such as latent inhibition, has been highly informative in elucidating the cognitive mechanisms underpinning psychosis. Amphetamine administration potentiates dopaminergic signalling from the mesolimbic pathway to the nucleus accumbens and wider ventral striatum ( Weiner, 1990 ), and this has been shown to inhibit LI effects in rodents ( Weiner et al., 1996 ), albeit with effects moderated by type of paradigm ( Killcross et al., 1994 ). Furthermore, administration of both typical and atypical D 2 receptor antagonist antipsychotics induce enhancement of LI ( Alves and Silva, 2001 ; Dunn et al., 1993 ; Feldon and Weiner, 1991 ; Moran et al., 1996 ; Trimble et al., 1997 ). Attentional theories would predict that the effects of antipsychotics and amphetamines would be exerted during the pre- exposure period. However, such effects have been shown to be specific to administration during the conditioning phase ( Weiner et al., 1988 , 1984 ). Thus, this evidence would suggest that dopaminergic signalling does not wholly underpin the learning about irrelevant (unreinforced) stimuli but rather impacts effectively utilising this information during conditioning. 3. Latent Inhibition and Psychosis Psychosis is a frequently debilitating clinical phenomenon characterised by hallucinations and/or delusions and is a hallmark feature of disorders such as schizophrenia (and schizophrenia spectrum disorders) and is commonly seen other conditions such as bipolar disorder ( Arciniegas, 2015 ). LI has been studied in the context of psychosis in numerous studies to model the aberrant salience hypothesis of psychosis ( Baruch et al., 1988 ; Gray et al., 2003 ; Kapur, 2003 ). These results show LI to be attenuated in people with schizophrenia and those scoring highly on measures of schizotypy, albeit with some variability between studies, but most do not include sex as a biological variable ( Myles et al., 2023 ). The aberrant salience hypothesis of schizophrenia argues that directed attentional processes are dysfunctional in schizophrenia and alterations in dopaminergic signalling lead to misdirection of attention to irrelevant stimuli, resulting in hallucinations and delusions ( Kapur, 2003 ; Lubow, 2005 ). Increased striatal dopamine synthesis capacity and synaptic dopamine content have been observed in psychosis, with the striatum receiving input from a wider network of the thalamus, striatum, hippocampus and prefrontal cortex ( Kesby et al., 2018 ). Prediction error and computational Bayesian theories explaining the altered dopaminergic signalling observed in psychosis assert that the dysfunctional dopaminergic signalling observed in psychosis leads to prediction errors encoding irrelevant stimuli as salient, i.e., aberrant salience ( Diederen and Fletcher, 2021 ; Howes et al., 2020 ). Thus, LI deficits in psychosis may arise from altered dopaminergic signalling resulting in previously pre-exposed irrelevant stimuli having inappropriately high associability due to disrupted prediction error processing. A large body of literature has revealed sex differences in psychosis in schizophrenia and bipolar disorder. Schizophrenia has a higher prevalence ( Aleman et al., 2003 ) and earlier age of onset ( Abel et al., 2010 ) in male compared to female individuals. Differences have also been observed between sexes in relation to pattern of symptoms, number of psychotic episodes, and comorbid psychopathologies ( Abel et al., 2010 ; Grossman et al., 2008 ). In healthy individuals, subclinical psychotic experiences appear to be more prevalent in male than female individuals during adolescence, but by early adulthood this sex difference disappears ( Spauwen et al., 2003 ). However, middle age represents a risk period for psychosis development in women, and women make up the majority of diagnoses at or post middle age, a finding which is thought to be attributable to hormonal changes occurring during the menopause ( Culbert et al., 2022 ). However, the majority of studies relating to biological and cognitive mechanisms underpinning psychosis did not consider sex as a biological variable ( Shansky and Murphy, 2021 ), and in a recent review of LI studies, sex differences were not assessed in the majority of studies ( Myles et al., 2023 ). Hence, owing to the extensive findings of sex differences in the severity and characterisation of symptoms in psychotic illnesses, it is crucial that we ascertain whether the underlying cognitive and neurobiological mechanisms of psychopathology are sexually dimorphic. 4. Systematic Review of Sex Differences in Latent Inhibition 4.1. Methods 4.1.1. Search strategy This systematic review aimed to evaluate whether sex differences have been identified in the existing latent inhibition literature in both human and rodent (rat and mouse) experiments. “Latent inhibition” was entered as a search term into SCOPUS, Web of Science, PUBMED and Science Direct databases with all results retained for screening. Although LI in humans has been studied largely in the context of psychosis, this review aimed to assess any LI study in humans regardless of clinical status of sample. Subsequently, any studies in samples of individuals with psychosis (e.g, schizophrenia, bipolar disorder or schizoaffective disorder), clinical samples of individuals with other psychiatric conditions, and any non-clinical samples were assessed, including studies investigating the impact of schizotypy on LI in non-clinical samples. Schizotypy refers to a multi-dimensional personality construct rather than a clinical diagnosis, characterised by cognitive-perceptual (e.g., odd beliefs, hallucinations), negative (e.g. anhedonia, alogia) and disorganised (e.g., thought disturbances, disorganised actions) experiences ( Kwapil and Barrantes-Vidal, 2015 ). High schizotypal individuals have been shown to be at increased risk for developing psychosis, and studying schizotypy in non-clinical samples allows for a wider exploration of the aetiology of the disorder ( Barrantes-Vidal et al., 2015 ). It is important to note that although sex and gender are distinct constructs, the terminology of gender and sex have largely been used without distinction within the studies reviewed. In this review, the term ‘sex’, with the binary of ‘male’ and ‘female’ will be used to refer to human participants, as this binary categorisation has been used within the literature, irrespective of whether the term ‘sex’ or ‘gender’ has been used. It is acknowledged that this categorisation does not correspond to the full spectrum of gender, hence the term gender is not used here. Those identifying as a gender that does not correspond to their assigned sex at birth, or are intersex, may have been included in studies reviewed here based on their gender identity rather than their assigned sex at birth, however this is expected to affect only a very small number of participants. 4.1.2. Study screening and selection Results were filtered to remove entries that were not journal articles, and any articles not in English, as well as any duplicated studies. All studies were then screened to identify those that included both male and female participants/animals. Studies were then assessed for eligibility based on the following criteria: a) to only include those that compared a CS or context pre-exposure condition with a non-pre-exposure condition (either between- or within-subject); b) LI independently assessed in males and females, or LI is statistically compared between sexes; c) LI was not assessed using a conditioned taste aversion (CTA) paradigm, as in this unique method the US does not arise until after a considerable delay from presentation of the CS, and the neurobiological underpinnings of CTA are thought to be distinct from other forms of classical conditioning ( Chambers, 1990 ). 4.1.3. Data extraction If a comparison between pre-exposure conditions was used in the study (i.e., pre-exposed vs non- pre-exposed conditions), the interaction between sex and PE condition was assessed. Alternatively, in studies using a metric for LI, such as a ratio or score as the dependent variable, the main effect of sex on this variable was assessed. The interaction between these effects and any further variables were also assessed and reported below. No metanalysis of data was conducted as this review is qualitative in nature. 4.2. Results 4.2.1. Systematic review 8908 records were returned after the initial search of the four data bases. After removing any items that were not in English, were not journal articles, or were duplicate items, 4070 records remained. These were screened to only retain records that were studies in either humans, rats or mice that included both male and female participants/animals, resulting in 1057 studies. The following inclusion criteria were used to retrieve the final set of studies: a) a direct comparison between a CS or context pre-exposure and a non-pre-exposure condition (either within- or between-subject); b) LI independently assessed in males and females, or LI is statistically compared between sexes; c) LI was not assessed using a CTA paradigm. 28 studies using human participants and 55 studies using rats or mice remained. The results of the review process are outlined in Figure 1 . Download figure Open in new tab Figure 1. Systematic review process. 4.2.2. Review of human studies 33 experiments across 28 separate studies were found ( Table 1 ) and used either visual or auditory LI tasks with either response reaction time or trials to learning criteria as the dependent variable. In visual LI tasks, either shapes or letters were used as the CS, and a specific target shape or the letter X was used as the US. In response reaction time designs, participants are instructed to press a button when either the X or target shape appears on screen. During the pre-exposure phase, letters/shapes are successively presented on screen with no target, and additional distractor letters/shapes are included as well as the cue letters/shapes. During the test phase, the cue letter/shape is presented prior to the target with distractor letters/shapes presented between cue-target pairings. In trials to learning criteria designs, cues are similarly pre-exposed depending on the condition, and participants are asked to indicate via button-press when they expect the target to appear. The number of trials required to achieve a set number of correct responses is used as the dependent variable. In within- subject designs, one cue will be presented during the pre-exposure phase (pre-exposed cue), and another cue will only be presented during the test phase (non-pre-exposed cue). LI is demonstrated if the participant is faster to respond to the non-pre-exposed cue compared with the pre-exposed cue (reaction time tasks) or takes fewer trials to learning criteria in the non-pre-exposed compared to pre-exposed condition (trials to learning criteria tasks). Auditory designs use the same principles, but cues are typically white noise tones, and targets and distractors are typically nonsense syllables. View this table: View inline View popup Table 1. Results of the systematic review of sex differences in latent inhibition in humans. The majority of experiments (22/33) assessed LI in non-clinical samples, with or without assessing the effect of schizotypy on LI. In the 10 non-clinical experiments that did not assess the impact of schizotypy, no sex differences in LI were found in any study. However, when the effect of schizotypy was considered, results are inconsistent. Seven experiments across six studies did not show sex differences in the effects of schizotypy on LI or main effects of sex on LI. Two studies in the same group showed high schizotypy potentiated LI in males but attenuated it in females ( Lubow et al., 2001 ; Lubow and De la Casa, 2002 ). However, the opposite finding was observed in a later study by the same group, whereby high-schizotypal male and low-schizotypal female participants did not show LI ( Kaplan and Lubow, 2011 ). Shrira and Kaplan (2009) assessed the effect of specific schizotypy dimensions and found an interaction between sex and schizotypy specifically in the cognitive- perceptual, but not interpersonal dimension, with high scoring males and low scoring females showing attenuated LI. Lee and Telch (2010) did not observe an interaction between sex and schizotypy, but did find a main effect of sex, with greater LI demonstrated in female compared with male participants, contrasting the findings of the studies in non-clinical samples that did not assess schizotypy. In schizophrenia clinical samples, sex differences in LI are often unclear due to incomplete reporting of data, such as only main effects of sex being evaluated rather than interactions between sex and patient/control status or interactions between sex or medication status. Hence, it cannot be discerned from these studies whether any disruption of LI specifically in schizophrenia differs according to sex. Notwithstanding, no overall sex effects were seen in the majority of studies (4/6). However, one study showed reversal of LI learning in female schizophrenia patients ( Lubow et al., 2000 ), and another did not find an interaction between sex and schizophrenia patient/control status but did show a tendency towards stronger LI in females compared with males across all participants ( Gal et al., 2009 ). Five studies in other clinical samples were found, none of which showed sex differences in LI ( Györfi et al., 2017 ; Lubow et al., 1999 ; R E Lubow et al., 2000 ; Lubow and Josman, 1993 ; Swerdlow et al., 1999 ). Overall, no evidence for sex differences was found in non-clinical samples that did not assess schizotypy. However, in studies assessing the effect of schizotypy in non-clinical samples, there was mixed evidence for an effect of sex. In clinical samples of individuals with schizophrenia, there was also mixed evidence for an effect of sex, but no evidence for an effect of sex in studies in other clinical samples. Thus, although there are some examples of sex differences in LI in human studies, the evidence currently available is inconclusive. 4.2.3. Review of rodent model studies Although latent inhibition has been extensively studied in rodents for several decades, only a minority of studies have used both male and female animals, and only a subset of those have also included sex as a factor in statistical analyses. In this review, a total of 60 experiments across 55 studies that met the inclusion criteria were identified ( Table 2 ). View this table: View inline View popup Table 2. Results of the systematic review of sex differences in latent inhibition in rodents. OVX: ovariectomisation. A range of behavioural paradigms were used across LI studies in rodents. Most experiments assessed cued, rather than contextual conditioning, typically using a neutral CS of a tone or light (51/60). The most common cued conditioning paradigm was CER (26/60), in which water-restricted animals are able to consume water, and the suppression of drinking behaviour in response to the CS is used as a measure of CS-US conditioning. Fourteen experiments used active avoidance paradigms, in which animals are able to escape from the compartment in which they underwent conditioning to a separate compartment, and escape responses to the CS is used as a measure of conditioning. Four passive avoidance experiments were identified, all of which assessed contextual, rather than cued conditioning. In such studies, animals are conditioned in one compartment of a two-way conditioning chamber, and at recall are returned to the other compartment. The latency to enter the compartment in which conditioning with the foot-shock occurred is used as the measure of fear conditioning. In twelve experiments, freezing behaviour was used as a measure of fear conditioning, seven of which used cued conditioning paradigms, three used contextual conditioning paradigms, and two tested both cued and contextual conditioning. In cued fear conditioning experiments measuring freezing, a foot-shock US is paired with the neutral CS, and at recall, the duration of the session in which the animal exhibits freezing behaviour is measured. In equivalent contextual conditioning studies, contextual fear conditioning can either be foreground or background ( Phillips and LeDoux, 1994 ). In background CFC, the US is paired with a discrete cue CS, but CFC is assessed by measuring time spent freezing when the animal is returned to the context in which conditioning occurred. Conversely, in foreground CFC, there is no discrete cue CS, and the context is the only predictor of the US. Once again, CFC is measured by the duration spent freezing when the animal is returned to the context. Four studies used appetitive rather than fear based conditioning models in which the animal develops an association between the CS and a food-based US, all of which assessed cued conditioning. Across all paradigms used, cued or contextual, using rat or mouse models, the majority of studies did not find sex differences in LI (37/60 experiments). Sex differences were found in wild-type animals at baseline in a minority of experiments, four of which showed stronger LI in females compared with males ( Boakes et al., 2000 ; Lehmann et al., 2002 , 2000a ; Meyer et al., 2006 ), whereas two studies showed stronger LI in males compared with females ( Marks et al., 2016 ; Weiss et al., 2001 ). However, in numerous instances, sex was found to interact with an additional variable to affect LI, such as genotype, juvenile handling or drug administration. Nine CER experiments demonstrated interactions with sex across juvenile handling ( Feldon and Weiner, 1988 ; Peters et al., 1991 ; Shalev et al., 1998 ; Weiner et al., 1987 ), corticosterone ( Shalev and Weiner, 2001 ), domoic acid ( Marriott et al., 2014 ), and polyI:C ( Arad et al., 2017 ; Piontkewitz et al., 2011 ) administration, and D1 receptor genotype ( Bay-Richter et al., 2009 ). Such interactions were also found in passive avoidance studies, with sex differences seen in the effects of polyI:C administration ( Bitanihirwe et al., 2010 ) and juvenile handling ( Weiner et al., 1985 ) on LI. However, when measuring freezing as a behavioural response, Meyer et al. (2006) did not find that sex interacted with polyI:C treatment condition to affect LI. In passive avoidance models, Huang et al. (2017) assessed the impact of NMDA and MK-801 administration on LI and reported an interaction between sex and drug administration on LI, however specific post hoc comparisons were not reported. Interactions between drug administration and sex on LI were also seen by Wang et al. (2012) in the case of ascorbic acid, methamphetamine, but not apomorphine. Five studies (all CER paradigms) assessed the effect of oestrous phase or ovariectomisation and oestrogen replacement in females on LI, all of which showed differences ( Almey et al., 2013 ; Arad and Weiner, 2010a , 2008 ; Nofrey et al., 2008 ; Quinlan et al., 2010 ). Female rats in oestrus during the pre-exposure stage and metestrus during the conditioning stage demonstrated LI but not during the other phases of the oestrus cycle ( Arad and Weiner, 2008 ). Furthermore, LI has been shown to be attenuated when conditioning takes place during proestrus compared with oestrus or metestrus ( Quinlan et al., 2010 ). LI has also been shown to be disrupted in ovariectomised female rats, a disruption that is then rescued by administration of high doses of 17b-oestradiol ( Arad and Weiner, 2009 ) (experiment not included in review table as only females were included in sample), mimicking the action of antipsychotics in restoring LI deficits induced by amphetamine ( Arad and Weiner, 2010b ). Oestrogen administration has also been found to enhance the benefit of antipsychotics in restoring LI in ovariectomised female rats ( Arad and Weiner, 2010a ). However, findings have not been wholly consistent, as Nofrey et al. (2008) observed disrupted LI in ovariectomised females administered with oestrogen benzoate whilst LI was intact in ovariectomised females administered with a vehicle and in males. Hence, the effects of oestrogen on latent inhibition may depend on dosage and type of oestrogen replacement administered. The complexity of this evidence suggests that possible sex differences in LI may be obscured by the effect of oestrus in females on LI. Fully characterising the influence of oestrogen on LI is crucial owing to half the population having a biological influence of oestrous hormones, and this is of particular relevance to psychosis, as a later life incidence peak of schizophrenia in women is observed at a time corresponding to menopause ( Jones, 2013 ). Furthermore, the effect of oestrous replacement in ovariectomised females was found to interact with administration of the antipsychotic haloperidol ( Almey et al., 2013 ), raising further implications for sex differences in mechanisms underpinning psychosis. Taken together, the results of the systematic review of LI in rodent studies show a mixed profile of evidence. Most studies included in the review that assessed the effect of sex on LI without another interacting factor did not observe sex differences in LI. Conversely, many of the sex differences observed were in sex interacting with factors such as drug administration, juvenile handling and oestrogen in females. This is suggestive of possible sexually dimorphic neurobiological substrates of LI, as LI functions similarly between sexes under baseline conditions, but sexes respond differentially to disruptive agents. In light of the limited evidence for sex differences in LI demonstrated in human studies, these findings of complex interactions between LI, sex, and additional variables highlight the value of rodent model studies for probing the underlying biological mechanisms that may lead to a sexually differentiated vulnerability to disruption of LI, even when performance under baseline conditions is similar between males and females. 5. Sex differences in the relationship between PE duration and LI of contextual fear memory The systematic review found limited evidence for sex differences in LI at baseline in humans and rodents. However, several rodent model studies assessed the impact of additional factors on LI such as drug administration, juvenile handling, and oestrous phase, and in many instances, interactions between the effects of sex and these additional factors on LI were observed. Hence, although LI performance may be equivalent between males and females at baseline, there is evidence for differential susceptibility for disruption to LI across numerous factors. Consequently, owing to the relevance of LI to cognitive processing underpinning psychosis, it is important to understand the basis for this sexually differentiated vulnerability. The formation of configural representations of contexts is mediated by the hippocampus ( Smith and Bulkin, 2014 ), and the hippocampus is also crucial for the formation of associations between context and CS, resulting in the context-dependency of cued fear conditioning and LI ( Bouton, 1993 ), as well as the formation of associations between context and US in CFC and the LI of CFC ( Chang and Liang, 2017 ). Foundational studies on sex differences in behavioural, molecular and circuit mechanisms of memory have used foreground CFC to show that the optimal training conditions and the molecular and circuit mechanisms supporting learning may differ between males and females ( Tronson and Keiser, 2019 ). Hence, here we have further explored sex differences in both the behavioural and hippocampal molecular underpinnings of LI using a CFC paradigm. We compared LI of CFC in male and female Sprague-Dawley rats across a range of context pre- exposure (PE) durations (5, 20 or 60 minutes per day for three consecutive days), as outlined in Figure 2 . ARRIVE guidelines were adhered to, and ethical approval was obtained from the Cardiff University Animal Welfare and Ethical Review Body. Download figure Open in new tab Figure 2. Outline of experimental protocol. PE: pre-exposure; CFC: contextual fear conditioning; CA1: cornu Ammonis 1 region of the hippocampus. 8 male and 8 female adult Sprague-Dawley rats were included in each PE duration group. Rats were pre-exposed to the conditioning chamber for either 5, 20 or 60 minutes each day over three days. 24 hours after the last PE session, rats underwent CFC, which consisted of two minutes in the conditioning chamber, a 2-second 0.64mA scrambled foot- shock, then a further minute in the conditioning chamber. 48 hours after the CFC session, rats were returned to the conditioning chamber for a 10-minute recall session, then a further 48 hours later were returned for a 2-minute recall session. 30 minutes after this second recall session, rats were euthanised using rising concentration of CO 2 . Brains were immediately extracted and flash frozen for later CA1 RNA-extraction and qPCR. All phases of the experiment were undertaken at the same time each day for each rat. Outcome measures assessed were percentage of time spent freezing in each recall session, and gene expression of Cfos and Bdnf-IX 30-minutes after the 2-minute recall session, as measured by qPCR. We showed that in both the 10-minute recall session (48 hours after CFC) and the 2-minute recall session (48 hours after 10min recall), pre-exposure conditions impacted freezing behaviour as an index of contextual fear memory, and this differed between males and females ( Figure 3 A and B). Specifically, during the 10-minute recall session, there was a significant interaction between Sex and PE duration ( F = 3.501, p = 0.032). There was also a significant main effect of PE duration ( F = 9.895, p < 0.001), but no main effect of Sex ( F = 0.196, p = 0.658). A significant interaction between Sex and PE duration was also found 48 hours later during the 2-minute recall session ( F = 3.778, p = 0.031). In this session there was no main effect of PE duration ( F = 2.056, p = 0.141) or Sex ( F = 0.134, p = 0.716). In both recall sessions, these interactions manifested as an expected reduction in contextual fear memory, and greater LI, with increasing durations of pre-conditioning context pre-exposure in males, but not females. Interestingly, in females the highest levels of freezing, and least LI, were seen in the 20min PE group, particularly evidenced during the first recall session. Download figure Open in new tab Figure 3. Two-way ANOVAs showed significant interactions between Sex and PE Duration for freezing behaviour during both the ten-minute (A) and two-minute (B) recall sessions, and in Bdnf-IX (C) and Cfos (D) gene expression in the CA1 region of the hippocampus 30 minutes after extinction recall. Behaviour: n = 8 per group (48 total). qPCR: n = 8 per group except 20min and 60min male (n = 7) (46 total). * = p < 0.05; ** = p < 0.01; *** = p < 0.001. Thirty-minutes after the second recall session the expression of the immediate early genes Cfos , a marker of neuronal activity, and Bdnf-IX , which is known to regulate synaptic plasticity was measured in the CA1 region of the hippocampus using qPCR. This region is particularly crucial to formation of contextual representations and plasticity processes underpinning learning and memory in the CA1 have been shown to be sexually dimorphic ( Qi et al., 2016 ). These molecular targets were selected to assess whether the behavioural findings were underpinned by a Sex X PE-duration interaction in both activation ( Cfos ) and synaptic plasticity processes indicative of learning ( Bdnf-IX) in the hippocampus. As was found in the behavioural measures, we showed that for both Bdnf-IX and Cfos expression, PE duration impacted gene expression in the CA1 region of the hippocampus in a manner that differed between sexes ( Figure 3 C and D). Specifically, there was a significant interaction between Sex and PE duration in Bdnf-IX ( F = 3.271, p = 0.048) and Cfos expression ( F = 5.796, p = 0.006). In Bdnf-IX expression, there was no main effect of Sex ( F = 0.250, p = 0.620) or PE Duration ( F = 0.222, p = 0.802). In Cfos expression, there was also a main effect of sex with greater expression in females compared with males ( F = 9.438, p = 0.004), but no main effect of PE duration ( F = 2.332, p = 0.110). Together, these behavioural and molecular findings suggest that the relationship between pre- exposure duration and strength of the LI effect differs between sexes. The existing literature on latent inhibition would suggest that longer pre-exposure durations would result in reduced strength of associative fear memories ( Lubow, 1989 ; Luchkina and Bolshakov, 2019 ), which would be reflected in a reduced fear response (i.e., freezing behaviour) when returning to the context compared to animals with shorter context pre-exposure durations. The data here show that to be the case in males, but not in females, highlighting that the findings of research conducted primarily in males are not necessarily generalisable to females. The Cfos data, a measure of hippocampal activity, particularly mirror the behavioural observations indicating a prominent role for hippocampal processing influencing LI performance. Bdnf-IX expression also appears to mirror behavioural findings in inverse. While both Cfos and Bdnf-IX expression show a similar interaction of sex with experience of context, the relationship between activity (cFos) and plasticity mechanisms associated with memory processes (BDNF) after fear and fear extinction memory recall remain to be determined. Together, these markers show that the sex differences in the relationship between context pre- exposure duration and strength of CFC and CFC extinction are reflected in molecular processes associated with both activity and learning in the hippocampus. 6. Discussion Despite several decades of study of latent inhibition, few studies have attempted to characterise sex differences in LI. Across both human and rodent LI studies, the majority of experiments did not reveal sex differences in LI. However, this was not a universal finding, and in a number of studies, sex differences were shown in the relationship between additional variables and LI. For instance, in humans several studies showed sex differences in the relationship between schizotypy in LI, albeit without a consistent direction of effect. In rodents, this was more extensively assessed, showing sex differences in the effects of factors such as juvenile handling and drug administration on LI. Furthermore, several rodent experiments observed differences in LI in females across phases of the oestrous cycle, or between ovariectomized females with and without oestrogen replacement. Thus, sex effects in LI may be related to a modulatory role of oestrogen on memory processing. No studies found in humans assessed the effects of sex hormones, and a lack of consideration of oestrous may contribute to sex differences not being shown in many studies. Taken together, these findings suggest that although LI may be comparable between males and females at baseline, males and females may be differentially susceptible to disruption of LI across both environmental and molecular variables. Fully characterising the sex differences in the neurobiological network underpinning LI (i.e., the striatum, hippocampus, mPFC and nucleus accumbens) will help to improve understanding of how this differential susceptibility to disruption of LI between sexes arises. Furthermore, future studies ought to ascertain the extent to which these differences are attributable to effects of oestrous. Discrepancies in whether sex differences are observed in LI between human and animal studies may be explained by differences in the specific methods of the paradigms used across species. Owing to important ethical considerations required in human studies and particularly those including patients, the stimuli used generally bear a neutral valence (e.g., letters on a screen or a flashing light). The use of similar tasks between studies allows for replicability and may have been adapted for use in scanners, facilitating assessment of the neurobiological underpinnings of LI. However, the psychotic phenomena that occur in psychosis often bear a negative valence and are fearful to the individual ( Gauntlett-Gilbert and Kuipers, 2005 ). Fear conditioning and the formation of fear associations is known to have a distinct neuronal circuitry heavily involving connectivity between the amygdala, hippocampus and pre-frontal cortex ( Delgado et al., 2008 ; Maren et al., 2013 ; Moustafa et al., 2013 ). Hence, if there is sexual dimorphism in this circuitry that is relevant to the formation of hallucinations and delusions but is not activated by the current array of LI tasks commonly used in humans, important sex differences in LI relevant to psychosis may be missed. The use of rodent models allows for the implementation of a wider range of conditioning paradigms than can be used in humans, including those that assess the latent inhibition of associative fear memory formation. LI may be also affected by sex differences in neural processing. We provide some evidence of this with a refined behavioural experiment specifically looking at hippocampal context memory formation and recall when we vary PE and using output measures at both behavioural and molecular levels. Females show different sensitivity to PE duration and hippocampal processing of memory after recall. In the literature review, only a small minority of the studies found assessed LI of contextual fear conditioning, rather than cued fear conditioning. However, CFC is a comparatively highly hippocampally dependent form of associative memory and, owing to the known sexual dimorphism of the hippocampus, it may be hypothesised that LI of this form of memory may be more susceptible to sex differences. Indeed, the work presented here show significant interactions between sex and pre-exposure duration, a finding which is associated with concurrent interactions between sex and pre-exposure duration in activity and synaptic plasticity markers ( Cfos and Bdnf-IX respectively) in the CA1 region of the hippocampus. Hence, cognitive processes and associated neurobiological substrates whereby pre-exposure information is utilised to inform associative learning that rely upon the hippocampus may differ between sexes. In order to elucidate these findings further, the approaches used ought to be extended, by assessing a wider range of brain regions (e.g., NAc, mPFC and amygdala) and CFC paradigms, and also explicitly considering oestrous phase. The molecular findings reported here come from memory recall post-extinction and further assessment is needed of the neurobiological underpinnings of the learning of contextual information during pre-exposure, and how this information is used during conditioning. Aberrant associative learning and memory mechanisms are thought to underpin the formation of hallucinations and delusions in disorders such as schizophrenia and bipolar disorder. Current pharmacological treatment options for psychosis are plagued with poor efficacy and significant side effects ( Haddad and Correll, 2018 ). Hence, it is crucial that novel precision treatment options that specifically target biologically causal mechanisms are developed. Recent transcriptomic analyses of psychosis GWAS data have revealed enrichments in genes highly expressed in the hippocampus as well as those involved in synaptic organisation, differentiation and transmission ( Trubetskoy et al., 2022 ). Hence, cellular and molecular mechanisms within the hippocampus may be a key target for novel pharmacological therapeutics. Developing our understanding of the sexually dimorphic nature of hippocampal-dependent cognition underpinning psychosis and its neurobiological substrates may help to explain the sex differences observed in disorders such as schizophrenia and bipolar disorder. Understanding the specific aetiology of neuropsychiatric disorders in both sexes will then facilitate the development of precision treatment approaches specific to both sexes. 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