Social fear extinction susceptibility is associated with Microbiota-Gut-Brain axis alterations.

Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses.

Correspondence to Antici et al. Salivary CRP predicts treatment response to virtual reality exposure therapy for social anxiety disorder.

The study by Antici et al. (2024) investigates the effects of virtual reality exposure therapy on social anxiety disorder (SAD), focusing on the relationship between C-reactive protein (CRP) levels in saliva and therapy outcomes. Findings indicate that this therapy not only reduces SAD symptoms and discomfort but also correlates with decreased systemic inflammation, as evidenced by lowered CRP levels. Remarkably, higher baseline CRP levels predicted a greater reduction in anxiety symptoms, suggesting a unique response pattern in SAD compared to other psychological disorders. This study highlights systemic inflammation's significance in SAD and the promise of non-invasive biomarkers like salivary CRP for managing psychological disorders. It calls for more research to understand the underlying mechanisms and validate these initial findings.

Generalized and social anxiety disorder interactomes show distinctive overlaps with striosome and matrix interactomes.

Mechanisms underlying anxiety disorders remain elusive despite the discovery of several associated genes. We constructed the protein-protein interaction networks (interactomes) of six anxiety disorders and noted enrichment for striatal expression among common genes in the interactomes. Five of these interactomes shared distinctive overlaps with the interactomes of genes that were differentially expressed in two striatal compartments (striosomes and matrix). Generalized anxiety disorder and social anxiety disorder interactomes showed exclusive and statistically significant overlaps with the striosome and matrix interactomes, respectively. Systematic gene expression analysis with the anxiety disorder interactomes constrained to contain only those genes that were shared with striatal compartment interactomes revealed a bifurcation among the disorders, which was influenced by the anterior cingulate cortex, nucleus accumbens, amygdala and hippocampus, and the dopaminergic signaling pathway. Our results indicate that the functionally distinct striatal pathways constituted by the striosome and the matrix may influence the etiological differentiation of various anxiety disorders.

Neuropeptide Y Reduces Social Fear in Male Mice: Involvement of Y1 and Y2 Receptors in the Dorsolateral Septum and Central Amygdala.

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 µL/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 µL/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.

Cortical activity during social acceptance and rejection task in social anxiety disorder: A controlled functional near infrared spectroscopy study.

BACKGROUND: The cognitive and emotional vulnerability of individuals with social anxiety disorder (SAD) and their response to repeated experiences of social rejection and social acceptance are important factors for the emergence and maintenance of symptoms of the disorder. Functional neuroimaging studies of SAD reveal hyperactivity in regions involved in the fear circuit such as amygdala, insula, anterior cingulate, and prefrontal cortices (PFC) in response to human faces with negative emotions. Observation of brain activity, however, involving studies of responses to standardized human interaction of social acceptance and social rejection have been lacking. METHODS: We compared a group of index subjects with SAD (N = 22, mean age:26.3 ± 5.4, female/male: 7/15) (SADG) with a group of healthy controls (CG) (N = 21, mean age:28.7 ± 4.5, female/male: 14/7) in measures of cortical activity during standardized experiences of human interaction involving social acceptance (SA) and social rejection (SR) video-simulated handshaking tasks performed by real actors. In a third, control condition (CC), the subjects were expected to press a switch button in an equivalent space. Subjects with a concurrent mood episode were excluded and the severity of subclinical depressive symptoms was controlled. 52-channel functional near-infrared spectroscopy (fNIRS) was used to measure cortical activity. RESULTS: Activity was higher in the SAD subjects compared to healthy controls, in particular in channels that project to middle and superior temporal gyri (STG), frontal eye fields (FEF) and dorsolateral prefrontal cortex (DLPFC) in terms of both SA and SR conditions. Cortical activity during the CC was not different between the groups. Only in the SAD-group, activity in the pre-motor and supplementary motor cortices, inferior and middle temporal gyri and fronto-polar area was higher during the rejection condition than the other two conditions. Anxiety scores were correlated with activity in STG, DLPFC, FEF and premotor cortex, while avoidance scores were correlated with activity in STG and FEF. CONCLUSIONS: SA and SR are represented differently in terms of cortical activity in SAD subjects compared to healthy controls. Higher activity in both social conditions in SAD subjects compared to controls may imply biological sensitivity to these experiences and may underscore the importance of increased cortical activity during social interaction experiences as a putative mediator of vulnerability to SAD. Higher cortical activity in the SADG may possibly indicate stronger need for inhibitory control mechanisms and higher recruitment of theory of mind functions during social stress. Higher activity during the SR compared to the SA condition in the SAD subjects may also suggest distinct processing of social cues, whether they involve acceptance or rejection.

Cortisol reactivity in social anxiety disorder: A highly standardized and controlled study.

In order to understand the psychopathology of the social anxiety disorder (SAD) at the neuroendocrine level, standardized experimental studies on endocrine and physiological markers are necessary, especially since empirical data are still ambiguous. Hence, differences in both, the autonomic nervous system (ANS) and the endocrine stress responses (ACTH, salivary and plasma cortisol) were investigated in a particularly homogenous sample after a standardized stressor (Trier Social Stress Test). The sample consisted of n = 35 patients with SAD, age, and gender matched to n = 35 healthy controls (HC). In terms of the heart rate, the response pattern was comparable in both groups. Concerning ACTH, no significant group differences in the response pattern nor in the total output (AUCG) were exhibited. Significant differences were noticeable only in the plasma cortisol response pattern with less total output (AUCG) in patients suggesting a blunted response. The salivary cortisol response indicated comparable patterns between groups. However, the patients' total output (AUCG) was significantly smaller relative to the controls. In sum, evidence for a hypo-responsiveness of the HPA-axis in SAD by means of blood cortisol was observed, with no differences in ACTH between the two groups. This reduced reactivity of the HPA-axis might be associated with an inability to elicit an adequate hormone release, possibly accompanied by an enhanced perception of the stress stimulus. This might be explained by an adaptation of the adrenocortical system due to prolonged repeated stress exposure such as social evaluation.

Endogenous in-session cortisol during exposure therapy predicts symptom improvement: Preliminary results from a scopolamine-augmentation trial.

The purpose of this study was to explore whether individual differences in glucocorticoid concentrations were associated with symptom improvement following exposure therapy for patients with social anxiety disorder. To do this, 60 participants with social anxiety disorder completed a randomized-controlled trial of exposure therapy, where participants were randomized to receive scopolamine-augmentation or placebo during their 7 exposure sessions. Scopolamine is an antimuscarinic which blocks the effects of acetylcholine and reduces autonomic arousal. During sessions 1, 4, 7, and during the post-treatment extinction assessment, participants provided up to 16 saliva samples (4 in each session). Pre-treatment, post-treatment, and at 1-month follow-up, participants completed the Liebowitz Social Anxiety Scale to monitor change in fear and avoidance symptoms. Elevated endogenous in-session cortisol during exposure sessions was associated with less symptom improvement from pre- to post-treatment and at 1-month follow-up. The association between elevated endogenous in-session cortisol and attenuated symptom change was not moderated by scopolamine treatment condition. Individuals with social anxiety disorder who have elevated neuroendocrine signaling may under-benefit from exposure therapy. This is the first study, to our knowledge, to examine whether endogenous in-session cortisol concentrations predict symptom changes following exposure therapy for the treatment of social anxiety disorder. More investigation of non-invasive and reliable biological markers that explain variability in responses to effective treatments are needed.

Endogenous testosterone levels are predictive of symptom reduction with exposure therapy in social anxiety disorder.

The Hypothalamus-Pituitary-Gonadal (HPG)-axis, and testosterone in particular, play an important role in social motivational behavior. Socially avoidant behavior, characteristic of social anxiety disorder (SAD), has been linked to low endogenous testosterone levels, and can be alleviated by testosterone administration in SAD. Although these beneficial effects of testosterone may translate to exposure therapy, it remains unknown whether testosterone increases prior to exposure improve therapy outcomes. In this proof-of-principle study, we tested whether pre-exposure (reactive and baseline) endogenous testosterone levels were predictive of exposure outcome in SAD. Seventy-three participants (52 females) with a principal SAD diagnosis performed four speech exposures: three during one standardized exposure therapy session and one at post-assessment one week later. Subjective fear levels were assessed before and after each speech exposure and social anxiety symptoms were assessed at pre- and post-treatment. Pre-treatment testosterone levels were assessed before (baseline) and in response to a pre-exposure instruction session (reactive). Pre-treatment testosterone levels were not related to fear levels during exposure therapy, but predicted pre- to post-treatment reductions in social anxiety symptom severity. Specifically, low baseline and high reactive pre-treatment testosterone levels were associated with larger reductions in social anxiety symptom severity. These findings support the role of HPG-axis in social fear reduction. Specifically, our finding that high reactive testosterone as well as low baseline testosterone predicted exposure outcome in SAD, suggests that good reactivity of the HPG-axis is a promising marker for the symptom-reducing effects of exposure therapy.

Modulation of the Endocannabinoid and Oxytocinergic Systems as a Potential Treatment Approach for Social Anxiety Disorder.

Social anxiety disorder (SAD), or social phobia, is one of the most common types of anxiety disorder, with a lifetime prevalence that can reach 15%. Pharmacological treatments for SAD have moderate efficacy and are associated with significant adverse reactions. Therefore, recent studies have focused on searching for new treatments for this disorder. Preclinical studies and preliminary evidence in humans suggest that the phytocannabinoid cannabidiol and the neuropeptide oxytocin have anxiolytic effects. In the present text, we review this evidence and its implications for pharmacological treatment. We conclude that although current available studies show promising results regarding both the safety and efficacy of cannabidiol and oxytocin for the treatment of SAD, most studies were performed using single or few doses of these compounds, with small sample sizes. Therefore, future studies should explore the anxiolytic potential of these compounds using long-term, placebo-controlled designs with larger samples to elucidate the possible use of these compounds in the treatment of SAD.

Repeated stress leads to enhanced cortisol stress response in child social anxiety disorder but this effect can be prevented with CBT.

Social anxiety disorder (SAD) is associated with continual social stress in everyday life. Two physiological components of stress are the hypothalamus-pituitary-adrenal axis, as captured by cortisol reactivity, and the autonomous nervous system, as captured by salivary alpha amylase (sAA) reactivity. In children with SAD, initial evidence points to dysregulated physiological stress reactivity for both systems. Furthermore, hardly any studies have assessed stress reactivity twice, including exploring possible changes after cognitive behavioral therapy (CBT). Children with SAD (n = 65; aged 9-13 years) and healthy controls (HCs, n = 55) participated in a social stress task (Trier Social Stress Test for Children, TSST-C), which was repeated with children with SAD after either 12 sessions of CBT or a waiting period to explore possible habituation or sensitization effects. Before treatment, children in the SAD and HC groups did not differ in their cortisol stress reactivity toward the TSST-C but did differ in their sAA response with a more pronounced response in the SAD group. After treatment, children with SAD in the waitlist group differed from children with SAD in the CBT group by showing stronger cortisol reactivity and a higher responder rate, indicative of a possible sensitization to stress. No difference was found for sAA. Future research should compare children with SAD and HC children concerning the effect of repeated stress on sensitization.

Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients.

Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC.

Frontal brain delta-beta correlation, salivary cortisol, and social anxiety in children.

BACKGROUND: Correlated activity of slow-wave (e.g. delta) and fast-wave (e.g. beta) frontal brain oscillations is thought to be an electrophysiological correlate of individual differences in neuroendocrine activity and anxiety in adult samples. We know, however, relatively little about the physiological and functional correlates of delta-beta coupling in children. METHOD: We examined whether longitudinal patterns of children's basal salivary cortisol and social anxiety across two visits separated by 1 year were associated with frontal brain delta-beta correlation in children (Mage  = 7.59 years, SD = 1.70). At Time 1 (T1), resting baseline electroencephalogram (EEG) recordings were collected from the children and delta and beta power was measured, and at both T1 and Time 2 (T2), basal salivary cortisol was measured, and parents reported on children's symptoms of social anxiety. RESULTS: Using latent class growth curve analysis, we found that children's salivary cortisol across visits was characterized by a high, stable class (53%), and a low, unstable class (47%), and children's social anxiety was characterized by a high, stable class (50%) and a low, stable class (50%). Using Fisher's r-to-z transformation, we found that frontal EEG delta-beta correlation was significantly stronger among children with high, stable salivary cortisol levels (compared to the low, unstable class; z = 2.11, p = .02), and among children with high, stable social anxiety levels (compared to the low, stable class; z = 1.72, p = .04). CONCLUSIONS: These findings demonstrate that longitudinal patterns of neuroendocrine stress activity and social anxiety may be associated with the correlation of EEG power in slow and fast frontal brain oscillations as early as childhood.

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders.

BACKGROUND: We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability. METHODS: We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo-controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12 weeks. RESULTS: Meta-analysis included 57 trials (N = 16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects. CONCLUSIONS: SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not.

Background cortisol versus social anxiety as correlates of HPA-axis recovery from stress in boys with Autism Spectrum Disorder.

Children with Autism Spectrum Disorder (ASD) show dysregulation of the expected Hypothalamus-Pituitary-Adrenal (HPA) axis and elevated cortisol responses to stress and response patterns, but little has been reported regarding their recovery from stress in terms of cortisol concentrations. This response was investigated in a sample of 32 young males with ASD aged between 9 and 18 years (M = 14.3 yr, SD = 2.7 yr), using a standardised experimental protocol combined with individualised stressor and non-stressor tasks. Results indicated that about half of the sample demonstrated unexpected HPA axis response patterns, and that recovery from stress cortisol concentrations were significantly associated with a single symptom of Social Phobia and Morning cortisol. These findings suggest that one of the key diagnostic criteria for ASD may be strongly influential in the HPA axis responses of boys with ASD and that training regimesto assist them to form less fearful associations with their non-ASD peers may be central to the academic and social progress of these boys.

Emotion regulation and biological stress responding: associations with worry, rumination, and reappraisal.

Individual differences in the habitual use of emotion regulation strategies may play a critical role in understanding psychological and biological stress reactivity and recovery in depression and anxiety. This study investigated the relation between the habitual use of different emotion regulation strategies and cortisol reactivity and recovery in healthy control individuals (CTL; n = 33) and in individuals diagnosed with social anxiety disorder (SAD; n = 41). The tendency to worry was associated with increased cortisol reactivity to a stressor across the full sample. Rumination was not associated with cortisol reactivity, despite its oft-reported similarities to worry. Worry and rumination, however, were associated with increased cortisol during recovery from the stressor. The only difference between CTL and SAD participants was observed for reappraisal. In the CTL but not in the SAD group, reappraisal predicted recovery, such that an increased tendency to reappraise was associated with greater cortisol recovery. These results suggest an important role of the habitual use of emotion regulation strategies in understanding biological stress reactivity and recovery.

Evidence for alterations of the right inferior and superior longitudinal fasciculi in patients with social anxiety disorder.

The aim of our study was to detect white matter (WM) regions being involved in the pathophysiology of SAD. We applied diffusion tensor imaging in 22 consecutive adult patients (11 women and 11 men) with SAD and 22 age and sex-matched healthy control subjects. We examined white matter (WM) alterations between the patients with social anxiety disorder (SAD) and healthy controls by a whole-brain analysis. We found that fractional anisotropy (FA) was reduced in patients with SAD compared with controls in the temporal part of right inferior longitudinal fasciculus (ILF) and the occipito-temporal part of the right superior longitudinal fasciculus (SLF). We also identified that in these regions FA was negatively correlated with the severity of anxiety. Our results suggest that the lateral temporal and occipito-temporal WM microstructure plays a role in mediating social interactions, and a pattern of WM abnormality in the right ILF and SLF may be implicated in the pathophysiology of SAD plausibly through leading to deficits in face processing mechanisms.

The relationship between dorsolateral prefrontal activation and speech performance-based social anxiety using functional near infrared spectroscopy.

Functional near-infrared (fNIR) spectroscopy is a promising new technology that has demonstrated utility in the study of normal human cognition. We utilized fNIR spectroscopy to examine the effect of social anxiety and performance on hemodynamic activity in the dorsolateral prefrontal cortex (DLPFC). Socially phobic participants and non-clinical participants with varying levels of social anxiety completed a public speaking task in front of a small virtual audience while the DLPFC was being monitored by the fNIR device. The relationship between anxiety and both blood volume (BV) and deoxygenated hemoglobin (Hb) varied significantly as a function of speech performance, such that individuals with low social anxiety who performed well showed an increase in DLPFC activation relative to those who did not perform well. This result suggests that effortful thinking and/or efficient top-down inhibitory control may have been required to complete an impromptu speech task with good performance. In contrast, good performers who were highly socially anxious showed lower DLPFC activation relative to good performers who were low in social anxiety, suggesting autopilot thinking or less-effortful thinking. In poor performers, slight increases in DLPFC activation were observed from low to highly anxious individuals, which may reflect a shift from effortless thinking to heightened self-focused attention. Heightened self-focused attention, poor inhibitory control resulting in excessive fear or anxiety, or low motivation may lower performance. These results suggest that there can be different underlying mechanisms in the brain that affect the level of speech performance in individuals with varying degrees of social anxiety. This study highlights the utility of the fNIR device in the assessment of changes in DLPFC in response to exposure to realistic phobic stimuli, and further supports the potential utility of this technology in the study of the neurophysiology of anxiety disorders.

Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder.

Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

Conditioned odor aversion induces social anxiety towards females in wild-type and TrpC2 knockout male mice.

Female-emitted pheromonal inputs possess an intrinsic rewarding value for conspecific males, promoting approach and investigation of the potential mating partner. In mice these inputs are detected mainly by the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). We investigated the role of VNO-mediated inputs in experience-dependent plasticity of reproductive responses. We applied a sex-specific conditioned odor aversion (COA) paradigm on adult, wild-type (WT) male mice and on male mice impaired in VNO-mediated signal transduction (TrpC2-/- ). We found that WT males, which underwent COA to female-soiled bedding, lost their innate preference to female odors and presented lower motivation to approach a sexually receptive female. COA also abolished the testosterone surge normally seen following exposure to female odors. Moreover, the conditioned males displayed impairments in copulatory behaviors, which lasted for several weeks. Surprisingly, these males also exhibited phobic behaviors towards receptive females, including freezing and fleeing responses. In contrast, WT males which underwent COA specifically to male pheromones showed no change in olfactory preference and only a marginally significant elevation in intermale aggression. Finally, we show that TrpC2-/- males were able to acquire aversion to female-soiled bedding and presented similar behavioral alterations following COA in their responses to female cues. Our results demonstrate that the intrinsic rewarding value of female pheromones can be overridden through associative olfactory learning, which occurs independently of VNO inputs, probably through MOE signaling.

No effects of psychosocial stress on memory retrieval in non-treated young students with Generalized Social Phobia.

Generalized Social Phobia (GSP) is a common anxiety disorder that produces clear social life disruptions. There is no consensus on the specific processes involved in its development, but the role of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested. This study analyzed the effects of the cortisol response to the Trier Social Stress Test (TSST) on the memory retrieval of pictures with different emotional valences in 45 non-treated young students with GSP and 50 non-anxious (NA) subjects (mean=19.35years, SD=0.18). No differences were found in the cortisol response of GSP and NA subjects to the TSST and control sessions. In addition, psychosocial stress impaired memory retrieval in both the GSP and NA groups, with no differences between them. Regarding the sex factor, no effects were found in the cortisol response to the TSST. However, during the encoding session, GSP men had higher cortisol levels than GSP women and NA subjects. There was also a significant interaction between sex and stress exposure on memory retrieval. Women recognized more unpleasant and neutral pictures than men; however, under stress, the women's advantage disappeared, and the men's performance improved. Sex also interacted with social phobia on positive mood, with GSP women exposed to the TSST showing the lowest positive mood. These results suggest that GSP subjects do not present an HPA axis sensitization to psychosocial stress, and they emphasize the importance of Sex in understanding stress effects on memory.