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BACKGROUND Sexual minorities (e.g. lesbian, gay, bisexual) are at increased risk for alcohol use disorder (AUD) compared to heterosexuals. The minority stress model postulates that disparities in AUD stem, in part, from stress specific to sexual minorities (e.g. heterosexism). However, little research has examined psychophysiological markers of minority stress reactivity and how psychophysiological stress reactivity is associated with lifetime minority stress and alcohol use among sexual minorities. Emotion modulation of the startle response is a well-established paradigm for capturing psychophysiological stress reactivity under controlled laboratory conditions. Purpose: This preliminary study is the first to use the startle experimental paradigm to examine psychophysiological reactivity to stigma among sexual minorities. Procedures: Sexual minority participants (N = 20; 55% female), aged 18 to 27 years (M = 21.80, SD = 2.65), were recruited from the community. We compared startle reactivity in response to three types of stimuli (stigma, negative, and neutral) among heavy drinking sexual minority young adults. Although statistically underpowered, we also explored the associations between startle reactivity and self-reported drinking behaviors and lifetime minority stress. Results: Both stigma and general unpleasant stimuli produced more psychophysiological stress reactivity than neutral stimuli among sexual minorities. Psychophysiological stress reactivity was correlated with greater quantity of drinks reported on drinking days in the past month, but not greater frequency. Additionally, lifetime exposure to minority stress was associated with a blunted reactivity to stigma stimuli. Conclusions: These findings provide methodological advances and important implications for minority stress theory and alcohol use among sexual minorities.

Apart from self and conspecific odors, odors from other species also influence the affective states in laboratory mice (Mus musculus musculus) in their home cages and during experimental procedures, possibly inducing confusion and inconsistency in experimental data. Thus, it is important to detect the types of animal odors associated with housing, husbandry, and laboratory practice that can arouse different types of affective changes in mice. Here, we aimed to test the effectiveness of the acoustic startle reflex (ASR) in detecting changes in the affective states of laboratory mice due to animal-derived-odor as it has a non-zero baseline, and can be enhanced or attenuated by positive or negative affective shifts, respectively. We used ASR to examine the affective changes in mice that were induced by bedding odors and an alarm pheromone. The odor of bedding obtained from the mice' home cages significantly attenuated the ASR, suggesting positive affective shifts in the test mice, whereas that from bedding obtained from rat cages significantly enhanced the ASR, suggesting negative affective shifts. No significant changes in ASR were observed in mice presented with the odor of bedding obtained from cages of unfamiliar conspecifics. In contrast, there was significant ASR enhancement in mice exposed to volatile components of alarm pheromones trapped in water, suggesting negative affective shifts. Thus, our findings show that ASR may be a valuable tool in assessing the effects of odors on the affective states in laboratory mice.

We aimed to analyze the prepulse inhibition (PPI) and recovery rate (R) of the trigeminocervical reflex (TCR) in patients with cervical dystonia (CD).We enrolled 15 patients with CD and 16 healthy subjects. TCR was recorded over splenius capitis after infraorbital nerve stimulation. For TCR-PPI, we applied a prepulse stimulus to the left second finger 100 ms prior to the test stimulus and the percentage of change of response to test stimulus was calculated. For TCR-R, we applied paired infraorbital stimuli at interstimulus interval (ISIs) of 300 ms and the percentage of change of the second compared to the first response was calculated.TCR-PPI and TCR-R values were higher (less inhibition and greater recovery) on both sides in the patient group compared to healthy subjects. There was high correlation between TCR-PPI and TCR-R on both sides in patients with dystonia (p 0.005). We did not find any significant relationship between TCR-R or TCR-PPI and side of dystonic posture.We showed disturbed modulation of TCR in CD patients. In CD, a general inhibition of the inhibitory pathways and facilitation of the excitatory pathways occur. Although TCR was recorded directly on the affected muscles in CD, symmetric abnormal TCR findings in CD suggest that these findings are probably secondary to altered function of higher order centers rather than being directly related to the pathophysiological process.

Recent translational data suggest that deep brain stimulation (DBS) of the cortico-striato-thalamo-cortical (CSTC) loops improves sensorimotor gating in psychiatric disorders that show deficient prepulse inhibition (PPI), a robust operational measure of sensorimotor gating. To our knowledge we are the first to investigate this effect in patients with Tourette syndrome (TS). We measured PPI of the acoustic startle reflex in patients with TS (N = 10) or Obsessive-Compulsive Disorder (OCD) (N = 8) treated with DBS of the centromedian and ventro-oral internal thalamic nucleus and the anterior limb of internal capsule-nucleus accumbens area respectively, and aged- and gender-matched healthy controls (HC). PPI of the DBS groups was measured in randomized order in the ON and OFF stimulation condition. Statistical analysis revealed no significant difference in PPI (%) of patients with TS between ON (M = 20.5, SD = 14.9) and OFF (M = 25.2, SD = 29.7) condition. There were significantly reduced PPI levels in patients with TS in the ON condition compared to HC (M = 49.2, SD = 10.7), but no significant difference in PPI between TS in the OFF condition and HC. Furthermore, we found no significant stimulation or group effect for OCD and HC (OCD ON: M = 57.0, SD = 8.3; OCD OFF: 67.8, SD = 19.6; HC: M = 63.0, SD = 24.3). Our study has a number of limitations. Sample sizes are small due to the restricted patient collective. The study was not controlled for use of psychoactive medication or nicotine. Furthermore, we were not able to assess presurgical PPI measurements. In conclusion, we were able to show that PPI is impaired in patients with TS. This finding is in line with recent translational work. With respect to the OCD cohort we were not able to replicate our previously published data. A disability in sensorimotor gating plays a pivotal role in many psychiatric disorders therefore more research should be conducted to disentangle the potential and limitations of modulating sensorimotor gating via brain stimulation techniques.

Increasing evidence supports schizophrenia may be a neurodevelopmental and neurodegenerative disorder. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to have neuroprotective effects and be effective in treating neurodegenerative disorders including schizophrenia. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of fluoxetine on the sensorimotor gating deficit, a schizophrenia-like behavior in a neurodevelopmental schizophrenic mouse model induced by MK-801, an N-methyl-d-aspartate glutamate receptor antagonist. On postnatal day 7, mouse pups were treated with a total seven subcutaneous daily injections of MK-801 (1 mg/kg/day), followed by intraperitoneal injection of fluoxetine (5 or 10 mg/kg/day) starting on postnatal day 14 in the MK-801-injected mice for 4 weeks. The sensorimotor gating deficit in mice was measured by prepulse inhibition (PPI) behavioral test on postnatal day 43. After the behavioral test, the protein expression of brain-derived neurotrophic factor (BDNF) was measured by western blot or ELISA in the frontal cortex of mice. Our results showed fluoxetine attenuated PPI deficit and the decrease of cerebral BDNF expression in the MK-801-injected mice. These results suggest that fluoxetine can be used to treat sensorimotor gating deficit in a neurodevelopmental mouse model of schizophrenia, and the attenuating effect of fluoxetine on sensorimotor gating deficit may be related to fluoxetine’s neuroprotective effect targeting on the modulation of cerebral BDNF.

Humans with cervical spinal cord injury (SCI) often recover voluntary control of elbow flexors and, to a much lesser extent, elbow extensor muscles. The neural mechanisms underlying this asymmetrical recovery remain unknown. Anatomical and physiological evidence in animals and humans indicates that corticospinal and reticulospinal pathways differentially control elbow flexor and extensor motoneurons; therefore, it is possible that reorganization in these pathways contributes to the asymmetrical recovery of elbow muscles after SCI. To test this hypothesis, we examined motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the arm representation of the primary motor cortex, maximal voluntary contractions, the StartReact response (a shortening in reaction time evoked by a startling stimulus), and the effect of an acoustic startle cue on MEPs elicited by cervicomedullary stimulation (CMEPs) on biceps and triceps brachii in males and females with and without chronic cervical incomplete SCI. We found that SCI participants showed similar MEPs and maximal voluntary contractions in biceps but smaller responses in triceps compared with controls, suggesting reduced corticospinal inputs to elbow extensors. The StartReact and CMEP facilitation was larger in biceps but similar to controls in triceps, suggesting enhanced reticulospinal inputs to elbow flexors. These findings support the hypothesis that the recovery of biceps after cervical SCI results, at least in part, from increased reticulospinal inputs and that the lack of these extra inputs combined with the loss of corticospinal drive contribute to the pronounced weakness found in triceps.SIGNIFICANCE STATEMENTAlthough a number of individuals with cervical incomplete spinal cord injury show limited functional recovery of elbow extensors compared with elbow flexor muscles, to date, the neural mechanisms underlying this asymmetrical recovery remain unknown. Here, we provide for the first time evidence for increased reticulospinal inputs to biceps but not triceps brachii and loss of corticospinal drive to triceps brachii in humans with tetraplegia. We propose that this reorganization in descending control contributes to the asymmetrical recovery between elbow flexor and extensor muscles after cervical spinal cord injury.

BACKGROUND AND PURPOSE Dysfunction of the prefrontal cortex (PFC) is involved in the cognitive deficits in neuropsychiatric diseases, such as schizophrenia, characterized by deficient neurotransmission known as NMDA receptor hypofrontality. Thus, enhancing prefrontal activity may alleviate hypofrontality-induced cognitive deficits. To test this hypothesis, we investigated the effect of forebrain-specific suppression or pharmacological inhibition of native Kv 7/KCNQ/M-current on glutamatergic hypofrontality induced by the NMDA receptor antagonist MK-801. EXPERIMENTAL APPROACH The forebrain-specific inhibition of native M-current was generated by transgenic expression, in mice, of a dominant-negative pore mutant G279S of Kv 7.2/KCNQ2 channels that suppresses channel function. A mouse model of cognitive impairment was established by single i.p. injection of 0.1 mg·kg-1 MK-801. Mouse models of prepulse inhibition (PPI) of acoustic startle reflex and Y-maze spontaneous alternation test were used for evaluation of cognitive behaviour. Hippocampal brain slice recordings of LTP were used to assess synaptic plasticity. Hippocampus and cortex were dissected for detecting protein expression using western blot analysis. KEY RESULTS Genetic suppression of Kv 7 channel function in the forebrain or pharmacological inhibition of Kv 7 channels by the specific blocker XE991 enhanced PPI and also alleviated MK-801 induced cognitive decline. XE991 also attenuated MK-801-induced LTP deficits and increased basal synaptic transmissions. Western blot analysis revealed that inhibiting Kv 7 channels resulted in elevation of pAkt1 and pGSK-3β expressions in both hippocampus and cortex. CONCLUSIONS AND IMPLICATIONS Both genetic and pharmacological inhibition of Kv 7 channels alleviated PPI and cognitive deficits. Mechanistically, inhibition of Kv 7 channels promotes synaptic transmission and activates Akt1/GSK-3β signalling.

Maternal immune activation (MIA) during pregnancy is associated with an increased risk of development of schizophrenia in later life. 17β-estradiol treatment may improve schizophrenia symptoms, but little is known about its efficacy on MIA-induced psychosis-like behavioural deficits in animals. Therefore, in this study we used the poly(I:C) neurodevelopmental model of schizophrenia to examine whether MIA-induced psychosis-like behavioural and neurochemical changes can be attenuated by chronic treatment (2-6 weeks) with 17β-estradiol. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15 and adult female offspring were tested for changes in prepulse inhibition (PPI) and density of dopamine D1 and D2 receptors and dopamine transporters in the forebrain compared to control offspring. Poly(I:C)-treated offspring exhibited significantly disrupted PPI, an effect which was reversed by chronic treatment with 17β-estradiol. In control offspring, but not poly(I:C) offspring, PPI was significantly reduced by acute treatment with either the dopamine D1/D2 receptor agonist, apomorphine, or dopamine releaser, methamphetamine. 17β-estradiol restored the effect of apomorphine, but not methamphetamine, on PPI in poly(I:C) offspring. There was a strong trend for a dopamine D2 receptor binding density increase in the nucleus accumbens core region in poly(I:C) offspring, and this was reversed by chronic 17β-estradiol treatment. No changes were found in the nucleus accumbens shell, caudate putamen or frontal cortex or in the density of dopamine D1 receptors or transporters. These findings suggest that 17β-estradiol may improve some symptoms of schizophrenia, an effect that may be mediated by selective changes in dopamine D2 receptor density.

Identifying neurobehavioral correlates of suicidal ideation can help detect those most vulnerable for suicide among high-risk groups, such as those with internalizing psychopathology. Individuals with elevated sensitivity to uncertain threat (U-threat) have a strong preference for known outcomes relative to unknown outcomes and often experience high levels of chronic distress. We therefore hypothesized that among individuals with internalizing psychopathology, those with heightened reactivity to U-threat would be especially prone to suicidal ideation as a means to escape uncertainty. The present study examined whether in two independent samples suicidal ideation was associated with heightened startle response to U-threat, and whether the effects were specific to responses U-threat relative to predictable threat (P-threat). Study 1 was a sample of treatment-seeking patients (N = 99) and Study 2 was a community sample (N = 102). Participants in both samples met current DSM-5 criteria for an anxiety and/or depressive disorder. In Study 1, current suicidal ideation was positively associated with startle potentiation to U-threat. Similarly, in Study 2, a lifetime history of suicidal ideation was positively associated with startle potentiation to U-threat. The relation between suicidal ideation and startle potentiation to U-threat remained when adjusting for number of internalizing diagnoses. Heightened reactivity to U-threat may therefore characterize those with a propensity for suicidal ideation among individuals with internalizing psychopathology.

Background: Given its emotional and autobiographical properties, music appears as a potential aid in diagnostic assessment and therapeutics in patients with disorders of consciousness (DOCs). Several studies have shown boosting effects on behavior and brain functioning when patients were exposed to (their preferred) music. Objective: The aim of this study was to investigate if these effects on the brain's spontaneous activity are dependent on the level of consciousness. Methods: Nine postcomatose patients and eight healthy control subjects were assessed using functional magnetic resonance imaging in two conditions: rest (without stimulation) and music. All patients presented at least an auditory startle, thereby suggesting the presence of residual auditory function. A gradient of consciousness (from unresponsive wakefulness syndrome to healthy subjects) was formulated to evaluate consciousness-level-dependent increases in brain activity and connectivity. Network-based functional connectivity assessed auditory, default-mode, frontoparietal, and music-evoked emotion networks. Furthermore, exploratory voxel-to-voxel analyses were performed at the whole brain level using intrinsic connectivity contrast and (fractional) amplitude of low-frequency fluctuations. Results: Stronger consciousness-level-dependent increases within network-to-voxel analysis of connectivity were found in the frontoparietal network with the precuneus during music stimulation compared with rest. Voxel-to-voxel analyses showed stronger increases of intrinsic connectivity in the music condition compared with rest in regions previously related to music processing. There were consistently more regions with increased connectivity during the main effect of music compared with rest. These increases of connectivity during music were observed in brain regions involved in consciousness, language, emotion, and memory processing. Conclusions: Our results show that music seems to trigger more substantial connectivity changes compared with rest, pointing toward the potential ability of music to stimulate patients' brain function. Further research should focus on effects of music in general, its specific acoustical features, and the effects of simple auditory stimuli, as well as the possible therapeutic and diagnostic effects of music in well-controlled clinical trials. Impact statement Due to its emotional and autobiographical properties, music is a particularly salient stimulus. A few studies using musical stimuli have shown promising results in terms of behavioral responsiveness in patients with disorders of consciousness (Magee, 2005; Raglio et al., 2014; Verger et al., 2014). Our study confirms the presence of a beneficial effect of music on brain connectivity in these severely brain-injured patients, which moreover seems to be dependent on the level of consciousness. Our findings therefore strengthen the hypothesis that music could play a role from a diagnostic and therapeutic standpoint in this population, paving the way for future well-controlled clinical trials.

Several lines of evidence suggest that chronic exposure to cannabinoids during adolescence may increase the risk of schizophrenia. Studies of the disorder have identified altered cortical dopaminergic neurotransmission. In this study, we hypothesised that heightened endocannabinoid system activation via chronic exposure to a highly potent cannabinoid receptors agonist in adolescent rats would cause long-lasting neurobiological changes that may dramatically alter expression and functions of dopamine metabolising enzymes, comethyl-o-transferase (COMT) and monoamine oxidases MAO-A and MAO-B. To test this hypothesis, adult male rats (70 PND) undergoing chronic treatment of the highly potent and non-selective CB agonist WIN55,212-2 (1.2 mg/kg) during adolescence (PND 30-50) were subjected after 20 days washout period to prepulse inhibition of acoustic startle test (PPI) to confirm cannabinoid-induced sensorimotor-gating impairments and afterwards examined for COMT, MAO-A and MAO-B expression and activity in the prefrontal cortex. Chronic WIN55,212-2 exposure during adolescence caused disruption of PPI, increased cortical dopamine level, decreased COMT mRNA expression and decreased MAO-A and MAO-B enzymatic activities. These results indicate that chronic exposure to cannabinoids during adolescence induces sensorimotor-gating alterations which likely result from changes in the prefrontal cortex dopaminergic signalling. This has important implications for developing methods of targeting dopamine metabolising enzymes and/or sequelae of its dysregulation in cannabinoid-induced schizoaffective-like behaviour.

Background Neonatal exposure to sevoflurane induces neurobehavioral and neuroendocrine abnormalities in exposed male rats (generation F0) and neurobehavioral, but not neuroendocrine, abnormalities in their male, but not female, offspring (generation F1). These effects of sevoflurane are accompanied by a hypermethylated neuron-specific K-2Cl (Kcc2) Cl exporter gene in the F0 spermatozoa and the F1 male hypothalamus, while the gene's expression is reduced in the F0 and F1 hypothalamus. We investigated whether inhibition of deoxyribonucleic acid methyltransferases (DNMTs) before paternal sevoflurane exposure could alleviate the anesthetic's F0 and F1 effects. Methods Sprague-Dawley male rats were anesthetized with 2.1% sevoflurane for 5 hours on postnatal day (P) 5 and mated with control females on P90 to generate offspring. The nonselective DNMT inhibitor decitabine (0.5 mg/kg, intraperitoneally) was administered 30 minutes before sevoflurane exposure. The F0 and F1 male rats were evaluated in in vivo and in vitro tests in adulthood. Results Paternal exposure to sevoflurane induced impaired prepulse inhibition of the acoustic startle response and exacerbated corticosterone responses to stress in F0 males and impaired prepulse inhibition of the startle responses in F1 males. These effects were accompanied in both generations by reduced and increased expressions of hypothalamic Kcc2 and Dnmt3a/b, respectively. Decitabine deterred the effects of paternal exposure to sevoflurane in F0 and F1 males. Conclusions These results suggest that similar decitabine-sensitive mechanisms regulating expression of multiple genes are involved in the mediation of neurobehavioral abnormalities in sires neonatally exposed to sevoflurane and in their future unexposed male offspring.

OBJECTIVE The aim was to demonstrate that antibodies from patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic-like features in mice. METHODS Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with CSF from patients or controls through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic-like behavior), memory, locomotor activity, and the density of cell-surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques. RESULTS In cultured neurons, CSF from patients, but not from controls, caused a significant decrease of cell-surface D1R and an increase of D2R clusters. In mice, CSF from patients caused a significant decrease of synaptic and total cell-surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic-like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of CSF from patients stopped. INTERPRETATION In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti-NMDAR encephalitis cause reversible psychotic-like features accompanied by changes (D1R decrease, D2R increase) in cell-surface dopamine receptor clusters. ANN NEUROL 2020 ANN NEUROL 2020;88:603-613.

Schizophrenia is a debilitating disorder affecting young adults displaying symptoms of cognitive impairment, anxiety, and early social isolation prior to episodes of auditory hallucinations. Cannabis use has been tied to schizophrenia-like symptoms, indicating that dysregulated endogenous cannabinoid signaling may be causally linked to schizophrenia. Previously, we reported that glutamatergic neuron-selective ablation of Lmo4, an endogenous inhibitor of the tyrosine phosphatase PTP1B, impairs endocannabinoid (eCB) production from the metabotropic glutamate receptor mGluR5. These Lmo4-deficient mice display anxiety-like behaviors that are alleviated by local shRNA knockdown or pharmacological inhibition of PTP1B that restores mGluR5-dependent eCB production in the amygdala. Here, we report that these Lmo4-deficient mice also display schizophrenia-like behaviors: impaired working memory assessed in the Y maze and defective sensory gating by prepulse inhibition of the acoustic startle response. Modulation of inhibitory inputs onto layer 2/3 pyramidal neurons of the prefrontal cortex relies on eCB signaling from the brain-derived neurotrophic factor receptor trkB, rather than mGluR5, and this mechanism was defective in Lmo4-deficient mice. Genetic ablation of PTP1B in the glutamatergic neurons lacking Lmo4 restored tyrosine phosphorylation of trkB, trkB-mediated eCB signaling, and ameliorated schizophrenia-like behaviors. Pharmacological inhibition of PTP1B with trodusquemine also restored trkB phosphorylation and improved schizophrenia-like behaviors by restoring eCB signaling, since the CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide blocked this effect. Thus, activation of PTP1B in pyramidal neurons contributes to schizophrenia-like behaviors in Lmo4-deficient mice and genetic or pharmacological intervention targeting PTP1B ameliorates schizophrenia-related deficits.

Anxiety disorders and symptoms disproportionately impact women relative to men, but it is unclear what mechanism(s) contribute to this phenomenon. The present study examined sensitivity to unpredictable threat as a potential mechanism of gender differences in panic symptoms. The sample included 67 participants (35 women) who completed the no, predictable, and unpredictable threat (NPU-threat) startle paradigm with electric shocks as the aversive stimulus. Participants also completed the self-report Inventory of Depression and Anxiety Symptoms to assess current panic and depression symptoms. Results indicated that women, relative to men, reported greater panic symptoms and demonstrated increased startle potentiation in anticipation of predictable and unpredictable threat. Furthermore, across all participants increased startle potentiation in anticipation of unpredictable (but not predictable) threat was associated with greater panic symptoms, but there was no relationship with depression symptoms. Finally, the gender difference in panic symptoms was mediated by startle potentiation in anticipation of unpredictable (but not predictable) threat. The present study suggests that a heightened sensitivity to unpredictable threat might be a mechanism that contributes to increased anxiety in women.

Dysregulated fear conditioned responses have been associated with PTSD in adults, with increased fear-potentiated startle (FPS) serving as a potential intermediate phenotype for PTSD risk. This phenotype has also been associated with stress-related ADCYAP1R1 gene variants in adult women. However, FPS and genotype have not yet been examined during development. The aim of this study was to examine developmental changes in fear conditioning, and to see whether these changes were impacted by genotype and trauma. Differential fear conditioning using FPS was tested in n = 63 children ages 8–13 at two visits (V1, V2) 1 year apart. Startle response was measured using electromyograph recordings of the eyeblink muscle. The rs2267735 SNP of the ADCYAP1R1 gene was extracted from genome-wide (GWAS) analyses. Trauma exposure was assessed using the Violence Exposure Scale-Revised (VEX-R). We found significant Visit by Genotype interactions, with CC genotype increasing FPS from V1 to V2. At V2 there was a Genotype by Violence interaction, with higher FPS in the CC vs G allele groups among those with higher violence exposure (F = 17.46, p = 0.0002). Females with the CC genotype had higher FPS compared to G allele females (F = 12.09, p = 0.002); there were no effects of genotype in males. This study showed Gene × Environment × Development and Gene × Sex effects of ADCYAP1R1 in a high-risk pediatric population. Those with the CC genotype and high levels of violence exposure, as well as females with the CC genotype, showed the greatest conditioned fear responses in adolescence.

Disorders of consciousness are challenging to diagnose. Hermann et al. identify a new clinical sign, the habituation of auditory startle reflex, which indexes the activity of a fronto-parietal network and predicts improved consciousness at 6 months. The measure could be a new bedside sign of minimally conscious state., Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)—also coined unresponsive wakefulness syndrome (UWS)—and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15–20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

Introduction: According to the fully-dimensional approach, schizotypy is a personality trait present in the population in a continuous manner while the quasi-dimensional approach emphasises its extreme presentations. In this study we examined the relationship between sensorimotor gating, a core risk-index of the schizophrenia-spectrum, and four schizotypal factors in a dimensional-wise and a dichotomising-wise approach. Methods: Two-hundred and eighty-three participants were assessed with the Schizotypal Personality Questionnaire and were tested for Prepulse Inhibition (PPI). Associations between the schizotypal factors and startle measures were examined with stepwise regressions (dimensional-wise approach). Individuals in the lower 20% or the upper 20% for each schizotypal factor were identified and between-group comparisons were conducted (dichotomising-wise approach). Results: We found that with both approaches, only high paranoid or negative schizotypy were associated with reduced PPI. The low negative schizotypy group had prolonged onset and peak latencies, indicating that prolonged stimulus detection accompanies superior sensorimotor gating in this group. Conclusions: The findings suggest that although differentiating the effects of the various schizotypal factors is primary, the approach employed is secondary. The study also adds evidence in the literature supporting PPI as a useful endophenotypic marker of the schizophrenia-spectrum and highlights the contribution of specific aspects of schizotypy.

Abnormal attentional and cognitive processes are thought to increase the risk for depression and anxiety. To improve understanding of brain mechanisms of anxiety and depressive disorders and condition of their comorbidity, the study of early attentional processes was provided.Participants were patients with depressive (80 s.), anxiety (69 s.), and comorbid (41 s.) disorders, and healthy volunteers (50 s.). Acoustic startle response (ASR) and P50 component of the auditory event-related potential were recorded.In the ASR model decreased startle response amplitude at the left eye in patients with comorbid disorder was found, and ASR latency was lengthened in all clinical groups. Deficit of prepulse inhibition was unique for comorbid disorder, and might be considered as risk of evolution to more serious condition. Reduced prepulse facilitation was revealed in patients with comorbid and anxiety disorders. In P50 suppression paradigm decreased S1 response amplitude was revealed in all clinical groups, P50 latency was prolonged in depressive and comorbid patients, and P50 suppression deficit was observed in depression and anxiety groups.The obtained results might be useful for development of integrative neural models of comorbidity of anxiety and depression, and elaboration of diagnostic and therapeutic approaches.

Aims Abstinence after chronic alcohol consumption leads to withdrawal symptoms, which are exacerbated after repeated cycles of relapse. This study examined withdrawal-like behaviors after chronic ethanol drinking, with or without repeated cycles of deprivation. Methods Male alcohol-preferring (P) rats had access to continuous ethanol (CE), chronic ethanol with repeated deprivation (RD), or remained ethanol naïve (EN). The RD group experienced seven cycles of 2 weeks of deprivation and 2 weeks of re-exposure to ethanol after an initial 6 weeks of ethanol access. Withdrawal was measured after an initial 24 h of ethanol re-exposure in the RD group, which coincided with the same day of ethanol access in the CE group. Withdrawal-like behavior was measured by (a) ethanol intake during the initial 24 h of re-exposure, (b) locomotor activity (LMA) in a novel field 9–13 h after removal of ethanol at the beginning of the fifth re-exposure cycle and (c) acoustic startle responding (ASR) 8–15 h after removal of ethanol at the beginning of the sixth re-exposure cycle. Results The RD rats displayed a 1-h alcohol deprivation effect (ADE) (temporary ethanol increase), relative to CE rats, during the first to fourth and seventh re-exposure cycles. RD and CE rats displayed significant increases in LMA than EN rats. Regarding ASR, RD rats displayed significantly greater ASR relative to EN rats. Conclusion This study confirms that P rats meet the animal model criterion for ethanol-associated dependence, without a reliance on either behavioral (limited fluid access) or pharmacological (seizure threshold manipulation) challenges.

Affective states are key determinants of animal welfare. Assessing such states under field conditions is thus an important goal in animal welfare science. The rapid Defence Cascade (DC) response (startle, freeze) to sudden unexpected stimuli is a potential indicator of animal affect; humans and rodents in negative affective states often show potentiated startle magnitude and freeze duration. To be a practical field welfare indicator, quick and easy measurement is necessary. Here we evaluate whether DC responses can be quantified in pigs using computer vision. 280 video clips of induced DC responses made by 12 pigs were analysed by eye to provide ‘ground truth’ measures of startle magnitude and freeze duration which were also estimated by (i) sparse feature tracking computer vision image analysis of 200 Hz video, (ii) load platform, (iii) Kinect depth camera, and (iv) Kinematic data. Image analysis data strongly predicted ground truth measures and were strongly positively correlated with these and all other estimates of DC responses. Characteristics of the DC-inducing stimulus, pig orientation relative to it, and ‘relaxed-tense’ pig behaviour prior to it moderated DC responses. Computer vision image analysis thus offers a practical approach to measuring pig DC responses, and potentially pig affect and welfare, under field conditions.

The ability to discriminate between danger and safety is crucial for survival across species. Whereas danger signals predict the onset of a potentially threatening event, safety signals indicate the non-occurrence of an aversive event, thereby reducing fear and stress responses. While the neural basis of conditioned safety remains to be elucidated, fear extinction studies provide evidence that the infralimbic cortex (IL) modulates fear inhibition. In the current study, the IL was temporarily inactivated with local muscimol injections in male and female rats. The effect of IL inactivation on the acquisition and expression of conditioned safety was investigated utilizing the startle response. Temporary inactivation of the IL prior to conditioning did not affect the acquisition of conditioned safety, whereas IL inactivation during the expression test completely blocked the expression of conditioned safety in male and female rats. Inactivation of the neighboring prelimbic (PL) cortex during the expression test did not affect the expression of safety memory. Our findings suggest that the IL is a critical brain region for the expression of safety memory. Because patients suffering from anxiety disorders are often unable to make use of safety cues to inhibit fear, the present findings are of clinical relevance and could potentially contribute to therapy optimization of anxiety-related psychiatric disorders. Electronic supplementary material The online version of this article (10.1007/s00213-020-05527-7) contains supplementary material, which is available to authorized users.

Background Alcohol misuse and post-traumatic stress disorder (PTSD) are highly comorbid, and treatment outcomes are worse in individuals with both conditions. Although more men report experiencing traumatic events than women, the lifetime prevalence of PTSD is twice as high in females. Despite these data trends in humans, preclinical studies of traumatic stress reactivity have been performed almost exclusively in male animals. Methods This study was designed to examine sex differences in traumatic stress reactivity in alcohol-naive rats (experiment 1) and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks (experiment 2). Animals were exposed to predator odor (bobcat urine) and tested for contextual avoidance 24 h later; unstressed controls were never exposed to predator odor. We evaluated changes in physiological arousal using the acoustic startle response (ASR) test at day 2 post-stress and anxiety-like behavior measured in the elevated plus-maze (EPM) at day 17 post-stress. In experiment 3, time course of corticosterone response was examined in male and female rats following exposure to predator odor stress. Results Alcohol-naive males and females exposed to predator odor displayed blunted weight gain 24 h post-stress, but only a subset of stressed animals exhibited avoidance behavior. In alcohol-drinking animals, the proportion of avoiders was higher in males than females, and predator odor exposure increased ASR in males only. Stressed females exhibited blunted ASR relative to unstressed females and stressed males, regardless of alcohol drinking history. Alcohol-experienced females presented lower anxiety-like behavior and higher general activity in the EPM in comparison with alcohol-experienced males. Plasma corticosterone levels were higher in females immediately after predator odor exposure until 60 min post-stress relative to males. Conclusions We report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, males with a history of chronic moderate alcohol drinking exhibited increased traumatic stress reactivity relative to alcohol-drinking females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior.

Aberrant threat reactivity has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD); however, the literature on this association is mixed. One factor that may contribute to this inconsistent association is differences in severity of posttraumatic stress symptoms (PTSSs) across studies, but no studies have tested this hypothesis. The relation between PTSD and threat reactivity may also differ between unpredictable threats (U-threats) and predictable threats (P-threats), given burgeoning evidence to support a particular role for aberrant responding to U-threat in PTSD. The present study examined how PTSS severity relates to startle potentiation to U-threat and P-threat in a trauma-exposed community sample (N = 258). There was a negative linear, but not quadratic, relation between PTSS severity and startle potentiation to U-threat, but not P-threat. Blunted defensive responding to U-threat may therefore contribute to higher levels of PTSSs and may represent a novel treatment target for higher levels of PTSSs.

Background: Prenatal stress has been shown to affect the cognition of offspring, including memory and learning abilities.Methods: In the current study, the long-term effects of chronic prenatal exp...

Hypothesis To develop a mouse model for temporary and persistent tinnitus using the gap startle paradigm. Background Behavioral animal models for tinnitus are classified into conditioning- and reflex-based types. Gap prepulse inhibition of the acoustic startle (GPIAS) is based on the acoustic startle modification by a silent gap and gap detection deficit caused by tinnitus gap filling. Methods We used C57BL/6J mice inherently susceptible to hearing loss and potentially predisposed to tinnitus. They were divided into the control, salicylate-induced tinnitus, and noise-induced tinnitus groups. Mice were tested with the auditory brainstem response at four frequencies (8, 16, 24, and 32 kHz) and GPIAS in three carrier conditions, 16 and 24 kHz narrow band noises (NBNs) and broadband noise, at multiple time points before and after treatment. The ratio between the gap startle and no-gap startle amplitudes was analyzed by a repeated measures design. In addition, the number of tinnitus-positive mice meeting a specified criterion was counted. Results Salicylate/unilateral noise trauma resulted in temporary/permanent tinnitus evidenced by GPIAS reduction. GPIAS reduction was the most significant at 16 kHz NBN among the three carriers in both tinnitus groups. Control mice also showed good gap detection performance at 16 kHz NBN, which is in the most sensitive hearing range in mice. Conclusion The GPIAS test in C57BL/6J mice was very reliable at 16 kHz NBN. This tinnitus model developed in the mouse strain of accelerated hearing loss can be used with two options of temporary and persistent tinnitus.

A fundamental task faced by the auditory system is the detection of events that are signaled by fluctuations in sound. Spiking in auditory cortical neurons is critical for sound detection, but the causal roles of specific cell types and circuits are still mostly unknown. Here we tested the role of a genetically identified population of layer 4 auditory cortical neurons in sound detection. We measured sound detection using a common variant of pre-pulse inhibition of the acoustic startle response, in which a silent gap in background noise acts as a cue that attenuates startle. We used a Gpr26-Cre driver line, which we found expressed predominantly in layer 4 of auditory cortex. Photostimulation of these cells, which were responsive to gaps in noise, was sufficient to attenuate the startle reflex. Photosuppression of these cells reduced neural responses to gaps throughout cortex, and impaired behavioral gap detection. These data demonstrate that cortical Gpr26 neurons are both necessary and sufficient for top–down modulation of the acoustic startle reflex, and are thus likely to be involved in sound detection.

Trace fear conditioning is an important research paradigm to model aversive learning in biological or clinical scenarios, where predictors (conditioned stimuli, CS) and aversive outcomes (unconditioned stimuli, US) are separated in time. The optimal measurement of human trace fear conditioning, and in particular of memory retention after consolidation, is currently unclear. We conducted two identical experiments (N1 = 28, N2 = 28) with a 15-s trace interval and a recall test 1 week after acquisition, while recording several psychophysiological observables. In a calibration approach, we explored which learning and memory measures distinguished CS+ and CS- in the first experiment and confirmed the most sensitive measures in the second experiment. We found that in the recall test without reinforcement, only fear-potentiated startle but not skin conductance, pupil size, heart period, or respiration amplitude, differentiated CS+ and CS-. During acquisition without startle probes, skin conductance responses and pupil size responses but not heart period or respiration amplitude differentiated CS+ and CS-. As a side finding, there was no evidence for extinction of fear-potentiated startle over 30 trials without reinforcement. These results may be useful to inform future substantive research using human trace fear conditioning protocols.

The tachykinin peptides include substance P (SP), neurokinin A and neurokinin B, which interact with three G-protein-coupled neurokinin receptors, NK1Rs, NK2Rs and NK3Rs, respectively. Whereas high densities of NK3Rs have been detected in the basolateral amygdala (BLA), the functions of NK3Rs in this brain region have not been determined. We found that activation of NK3Rs by application of the selective agonist, senktide, persistently excited BLA principal neurons. NK3R-elicited excitation of BLA neurons was mediated by activation of a non-selective cation channel and depression of the inwardly rectifying K

The cranial window technique has proven to be an effective method for in vivo imaging of cortical activity. However, given the invasive nature of this procedure, possible side effects could be expected in the nervous system. In this study, we evaluated the effects of unilateral cranial window surgery on auditory function in C57BL6 mice using electrophysiological and behavioral approaches. We found that one week after implantation, mice exhibited both increased thresholds and decreased amplitudes of their auditory brainstem responses. These changes were accompanied by a decrease in distortion product otoacoustic emissions, indicating a deterioration in cochlear function. In addition, behavioral testing of these mice revealed reduced suppression of their acoustic startle response by gap prepulse, suggesting a deficit in auditory processing or possibly the presence of tinnitus. The changes in auditory function appeared to be only partially reversible within four weeks after surgery. Thus, our findings suggest that cranial window implantation causes long-term functional changes in the auditory system that should be considered when interpreting data from optical imaging techniques.

Although individuals with schizophrenia typically present deficits in social interaction, little is known about the quality of their parent-infant interactions. In the present study, we assessed the behavioral effects of neonatal ventral hippocampus lesion (nVHL) in female rats (nVHL is known to induce schizophrenia-like deficits in males). Sexually naïve adult nVHL or sham female rats received cognitive and social tests, and their maternal behavior was observed in independent groups of adult nVHL and sham rats on postpartum days 2, 6, and 12. Compared to Sham females, naïve nVHL rats displayed elevated locomotor activity, less social interaction, and disrupted habituation of the acoustic startle response (ASR), while dorsal immobility (a defensive behavioral response) and prepulse inhibition of ASR were not affected. Although all nVHL mothers retrieved their pups, adopted the crouching posture, and nursed them, they showed disturbances in the display of pup body licking and nest building. Furthermore, a high proportion of nVHL mothers displayed atypical retrieval of pups and re-retrieving of pups, atypical nest-building, excavation, and cannibalism, as well a high level of these behaviors. These data indicate that cognition, locomotor activity, and maternal care is disrupted in nVHL female, suggesting disturbances in mesocorticolimbic dopaminergic systems and/or in social cognition.

Cognitive fatigue (CF) can result from sustained mental effort, is characterized by subjective feelings of exhaustion and cognitive performance deficits, and is associated with slowed simple reaction time (RT). This study determined whether declines in motor preparation underlie this RT effect. Motor preparation level was indexed using simple RT and the StartReact effect, wherein a prepared movement is involuntarily triggered at short latency by a startling acoustic stimulus (SAS). It was predicted that if decreased motor preparation underlies CF-associated RT increases, then an attenuated StartReact effect would be observed following cognitive task completion. Subjective fatigue assessment and a simple RT task were performed before and after a cognitively fatiguing task or non-fatiguing control intervention. On 25% of RT trials, a SAS replaced the go-signal to assess the StartReact effect. CF inducement was verified by significant declines in cognitive performance (p = 0.003), along with increases in subjective CF (p 0.001) and control RT (p = 0.018) following the cognitive fatigue intervention, but not the control intervention. No significant pre-to-post-test changes in SAS RT were observed, indicating that RT increases resulting from CF are not substantially associated with declines in motor preparation, and instead may be attributable to other stages of processing during a simple RT task.

Numerous studies in children, adolescents and adults have reported that anxiety disorders and symptoms are associated with greater threat-potentiated startle responses. This suggests that it may also be related to risk factors that have been implicated in the genesis of anxiety disorders. Therefore, we examined the roles of early childhood temperamental behavioral inhibition (BI) and parental history of anxiety disorders in predicting threat-potentiated startle response in a community sample of 346 adolescents. Parental history of anxiety disorders moderated the effects of BI on subsequent startle responses. For both total startle response and unpredictable threat startle potentiation, higher levels of BI at age 3 predicted larger startle responses at age 15, but only among offspring of parents with a history of anxiety disorders. Among offspring of parents with no lifetime history of anxiety disorder, BI was unrelated to startle magnitude. These findings were evident even after adjusting for youth's biological sex, concurrent anxiety symptoms, and lifetime history of anxiety disorders. In contrast, neither BI nor parental anxiety significantly predicted startle potentiation to predictable threat. These findings have implications for tracing pathways to the development of anxiety disorders.

Repeat-associated non-AUG translation (RAN translation) is observed in transcripts that are causative for polyglutamine (polyQ) diseases and generates proteins with mono amino acid tracts such as polyalanine (polyA), polyleucine (polyL) and polyserine (polyS) in neurons, astrocytes and microglia. We have previously shown that microglia with aggregated polyQ led to defective differentiation and degeneration of neuron-like cells. However, it has not been determined whether only microglia containing a specific RAN product, but not other RAN products, is harmful in vitro and in vivo. Here we show that polyL-incorporating microglia specifically led to altered startle response in mice. Aggregated polyA, polyS and polyL induced aberrant differentiation of microglia-like BV2 cells. Differentiated PC12 cells treated with conditioned medium (CM) of polyS- and polyL- but not polyA-incorporating microglia-like BV2 cells showed retraction of neurites and loss of branch of neurites. Injection of the polyL-CM, but not polyA-CM and polyS-CM, into the lateral ventricle lowered startle response in mice. Consistently, polyL induced the highest expression of CD68 in BV2 cells. The lowered startle response was replicated in mice given the polyL-CM in the caudal pontine reticular nucleus (PnC), the key region of startle response. Thus, endogenous RAN proteins having polyL derived from polyQ diseases-causative genes in microglia might specifically impair startle response.

Sensitivity to uncertain threat (U-threat) is a clinically important individual difference factor in multiple psychopathologies. Recent studies have implicated a specific frontolimbic circuit as a key network involved in the anticipation of aversive stimuli. In particular, the insula, thalamus, and dorsal anterior cingulate cortex (dACC) have recently been found to be robustly activated by anticipation of U-threat. However, no study to date has examined the association between U-threat reactivity and structural brain volume. In the present study, we utilized a pooled sample of 186 young adult volunteers who completed a structural MRI scan and the well-validated No-Predictable-Unpredictable (NPU) threat of electric shock task. Startle eyeblink potentiation was collected during the NPU task as an objective index of aversive reactivity. ROI-based analyses revealed that increased startle reactivity to U-threat was associated with reduced gray matter volume in the right insula and bilateral thalamus, but not the dACC. These results add to a growing literature implicating the insula and thalamus as core nodes involved in individual differences in U-threat reactivity.

Women with a history of adverse childhood experiences (ACEs) enter pregnancy and the postpartum with a physiologic system programmed by early life stress, potentially reflected in psychophysiologic reactivity.We enrolled pregnant, psychiatrically healthy women ≥18 years old. Using the ACE Questionnaire, women were categorized as high (≥2 ACEs; n = 77) or low ACE (2 ACEs; n = 72). Participants completed an affective modulation of acoustic startle response (ASR) task during pregnancy and postpartum, in which ASR magnitude was measured while participants viewed pleasant, unpleasant, and neutral pictures. Two types of control trials were included (habituation trials presented at baseline and intertrial interval trials presented when no picture was present).Among high ACE women, ASR was significantly higher postpartum compared with pregnancy in the unpleasant (p = 0.002, β = 0.46, 95% CI [0.18, 0.74], χPhysiological reactivity increased in high ACE women from pregnancy to postpartum, but no change was observed in low ACE women.

Classical views suggest that experienced affect is related to a specific bodily response, whereas recent perspectives challenge this view postulating that similar affective experiences rather evoke different physiological responses. To further advance this debate in the field, we used representational similarity analysis to investigate the correspondence between subjective affect (arousal and valence ratings) and physiological reactions (skin conductance response [SCR], startle blink response, heart rate, and corrugator activity) across various emotion induction contexts (picture viewing task, sound listening task, and imagery task). Significant similarities were exclusively observed between SCR and arousal in the picture viewing task. However, none of the other physiological measures showed a significant relation with valence and arousal ratings in any of the tasks. These findings are discussed within the framework of the Populations hypothesis, suggesting that physiological responses do not depend on the experienced affect but are directly associated with the context in which they are evoked.

Latrophilin-3 (LPHN3) is a brain specific G-protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3 variants are associated with some cases of ADHD. Lphn3 KO rats are hyperactive with an attenuated response to ADHD medication and have cognitive deficits. Here, we tested KO, heterozygous (HET), and wildtype (WT) rats to determine if there was a gene-dosage effect. We tested the rats in home-cage activity starting at postnatal day (P)35 and P50, followed by tests of egocentric learning (Cincinnati water maze [CWM]), spatial learning (Morris water maze [MWM]), working memory (radial water maze [RWM]), incidental learning (novel object recognition [NOR]), acoustic startle response (ASR) habituation, tactile startle response (TSR) habituation, prepulse modification of acoustic startle, shuttle-box passive avoidance, conditioned freezing, and a mirror image version of the CWM. KO and HET rats were hyperactive. KO and HET rats had egocentric (CWM) and spatial deficits (MWM), increased startle response, and KO rats showed less conditioned freezing on contextual and cued memory; there were no effects on working memory (RWM) or passive avoidance. The selective gene-dosage effect in Lphn3 HET rats indicates that Lphn3 exhibits dominate expression on functions where it is most abundantly expressed (striatum, hippocampus) but not on behaviors mediated by regions of low expression. The data add further evidence to the impact of this synaptic protein on brain function and behavior.

MDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, combined with psychotherapy has demonstrated efficacy for the treatment of chronic posttraumatic stress disorder (PTSD) patients. This controlled prospective study aimed to assess the bio-behavioral underpinnings of MDMA in a translational model of PTSD. Rats exposed to predator-scent stress (PSS) were subjected to a trauma-cue at day 7 shortly after single-dose MDMA injection (5 mg/kg). The elevated plus maze and acoustic startle response tests were assessed on day 14 and served for classification into behavioral response groups. Freezing response to a further trauma-reminder was assessed on Day 15. The morphological characteristics of the dentate gyrus (DG) and basolateral amygdala (BLA) were subsequently examined. Hypothalamic–pituitary–adrenal axis and 5-hydroxytryptamine involvement were evaluated using: (1) corticosterone measurements at 2 h and 4 h after MDMA treatment, (2) Lewis strain rats with blunted HPA-response and (3) pharmacological receptor-blockade. MDMA treatment was effective in attenuating stress behavioral responses only when paired with memory reactivation by a trauma-cue. The effects of the treatment on behavior were associated with a commensurate normalization of the dendritic cytoarchitecture of DG and BLA neurons. Pretreatment with RU486, Ketanserin, or Pindolol prevented the above improvement in anxiety-like behavioral responses. MDMA treatment paired with memory reactivation reduced the prevalence rate of PTSD-phenotype 14 days later and normalized the cytoarchitecture changes induced by PSS (in dendritic complexities) compared to saline control. MDMA treatment paired with a trauma-cue may modify or update the original traumatic memory trace through reconsolidation processes. These anxiolytic-like effects seem to involve the HPA axis and 5-HT systems.

Understanding factors that influence behavioral performance in high-pressure contexts is relevant to critical occupations such as first responders, military personnel, and frontline medical workers. A recent study by Yancey et al. (2019) demonstrated an association between boldness, a biobehavioral trait reflecting social dominance and fearlessness, and enhanced task-switching performance during threat of shock relative to a no-shock (safe) condition. This study used a sustained threat manipulation in which cues signaling possible shock were present throughout blocks of multiple task trials. Here, we extended this work by evaluating the relationship between boldness and task-switching performance under acute threat of shock conditions, in which cues signaling possible shock occurred during individual task trials, intermingled with safe trials. Participants (

Bimanual actions are typically initiated and executed in a temporally synchronous manner, likely due to planning bilateral commands as a single motor "program." Applying high-intensity transcranial magnetic stimulation (TMS) to the motor cortex can result in a contralateral cortical silent period that delays reaction time (RT), if timed to coincide with the final motor output stage. The current study examined the impact of a unilateral TMS silent period on the RT and interlimb timing of bilateral wrist extension. In addition, because a loud, startling acoustic stimulus (SAS) can result in the involuntary release of preprogrammed actions via increased reticulospinal activation, it was of interest whether startle-induced speeding of response initiation would moderate the impact of the TMS-induced RT delay. Participants performed blocks of unilateral and bilateral wrist extension in response to an acoustic (82 dB) go-signal. On selected trials, either TMS was applied to the left motor cortex 70 ms before the expected EMG response onset, a SAS (120 dB) replaced the go-signal, or both TMS and SAS were delivered. Results showed that TMS led to a significant RT delay in the right limb during both unimanual and bimanual extension but had no impact on the left limb initiation. In addition, the magnitude of the right limb RT delay was smaller when the response was triggered by a SAS. These results imply that preplanned bimanually synchronous movements are susceptible to lateralized dissociation late into the cortical motor output stage and movements triggered by startle involve increased reticulospinal output.

Fear conditioning paradigms are frequently used in the translational study of anxiety and fear-related disorders. Accordingly, it is important to understand whether the measurement of fear conditioning responses is systematically influenced by an individual's race. Studies have found increased pain sensitivity and smaller physiological startle responses in Asian individuals, compared to White individuals; to our knowledge, no studies have evaluated whether skin conductance response (SCR) outcomes differ between Asian and White individuals. In a series of secondary data analyses, we investigated potential differences in skin conductance level (SCL), orienting SCR, unconditioned SCR, SCR to CS+ and CS-, differential SCR, and differential SCR non-responder status. In sample 1, Asian participants (n = 97) demonstrated a significantly smaller mean differential SCR compared to White participants (n = 86). No other between group differences were observed. In sample 2, there was no difference in mean differential SCR between Asian (n = 52) and White (n = 62) participants, although more Asian participants failed to show adequate skin conductance levels for study entry. To our knowledge, this is the first study to evaluate differences between Asian and White samples using skin conductance outcomes in a fear conditioning paradigm. We detected only subtle evidence for SCR differences between Asian and White samples, unlikely to reach significance outside large studies.

The startle response consists of whole-body muscle contractions, eye-blink, accelerated heart rate, and freezing in response to a strong, sudden stimulus. It is evolutionarily preserved and can be observed in any animal that can perceive sensory signals, indicating the important protective function of startle. Startle response measurements and its alterations have become a valuable tool for exploring sensorimotor processes and sensory gating, especially in the context of pathologies of psychiatric disorders. The last reviews on the neural substrates underlying acoustic startle were published around 20 years ago. Advancements in methods and techniques have since allowed new insights into acoustic startle mechanisms. This review is focused on the neural circuitry that drives the primary acoustic startle response in mammals. However, there have also been very successful efforts to identify the acoustic startle pathway in other vertebrates and invertebrates in the past decades, so at the end we briefly summarize these studies and comment on the similarities and differences between species.

Tic related disorders affect 4–20% of the population, mostly idiopathic, can be grouped in a wide spectrum of severity, where the most severe end is Tourette Syndrome (TS). Tics are arrhythmic hyperkinesias to whom execution the subject is forced by a “premonitory urge” that can be classified as sensory tic, just-right experience or urge without obsession. If an intact volitional inhibition allows patients to temporarily suppress tics, a lack or deficit in automatic inhibition is involved in the genesis of the disorder. Studies have assessed the presence of intrinsic microscopic and macroscopic anomalies in striatal circuits and relative cortical areas in association with a hyperdopaminergic state in the basal forebrain. Prepulse inhibition (PPI) of the startle reflex is a measure of inhibitory functions by which a weak sensory stimulus inhibits the elicitation of a startle response determined by a sudden intense stimulus. It is considered an operation measure of sensorimotor gating, a neural process by which unnecessary stimuli are eliminated from awareness. Evidence points out that the limbic domain of the CSTC loops, dopamine and GABA receptors within the striatum play an important role in PPI modulation. It is conceivable that a sensorimotor gating deficit may be involved in the genesis of premonitory urge and symptoms. Therefore, correcting the sensorimotor gating deficit may be considered a target for tic-related disorders therapies; in such case PPI (as well as other indirect estimators of sensorimotor gating) could represent therapeutic impact predictors.

Ghrelin, a stomach-produced hormone, is well-recognized for its role in promoting feeding, controlling energy homeostasis, and glucoregulation. Ghrelin's function to ensure survival extends beyond that: its release parallels that of corticosterone, and ghrelin administration and fasting have an anxiolytic and antidepressant effect. This clearly suggests a role in stress and anxiety. However, most studies of ghrelin's effects on anxiety have been conducted exclusively on male rodents. Here, we hypothesize that female rats are wired for higher ghrelin sensitivity compared to males. To test this, we systematically compared components of the ghrelin axis between male and female Sprague Dawley rats. Next, we evaluated whether anxiety-like behavior and feeding response to endogenous or exogenous ghrelin are sex divergent. In line with our hypothesis, we show that female rats have higher serum levels of ghrelin and lower levels of the endogenous antagonist LEAP-2, compared to males. Furthermore, circulating ghrelin levels were partly dependent on estradiol; ovariectomy drastically reduced circulating ghrelin levels, which were partly restored by estradiol replacement. In contrast, orchiectomy did not affect circulating plasma ghrelin. Additionally, females expressed higher levels of the endogenous ghrelin receptor GHSR

Prepulse inhibition (PPI) refers to the diminution of the startle reflex to a sudden and intense acoustic stimulus (pulse) when this startle-eliciting pulse is preceded shortly by a weaker prepulse stimulus. PPI is widely used in evaluating the effects of psychomimetic and antipsychotic drugs on sensorimotor gating, but individual differences in PPI expression have received scant attention. We have previously shown that mice and rats exhibiting stronger motor response to the prepulse also exhibit more PPI. It remains unexplored, however, if this between-subjects correlation may be similarly observed across trials from a within-subjects perspective. Here, we mapped the prepulse-elicited response to the diminution of the startle response to the succeeding pulse stimulus, trial-by-trial, across nine prepulse-pulse definitions with varying prepulse and pulse intensities. The resulting within-subjects correlation independently obtained in 113 adult C57BL6 mice revealed that trials registering a stronger prepulse reaction also recorded a larger startle response to the pulse stimulus, indicative of weaker PPI, especially when higher-intensity prepulses were paired with low-intensity pulses. The within- and between-subjects analyses have apparently yielded two contrasting relationships between the direct motor response to the prepulse and the inhibition of subsequent startle reaction induced by the same prepulse. One interpretation is that the within-subjects correlation reflects state-dependent variation, whereas the between-subjects correlation stems from trait-dependent individual variation. Finally, whether our present findings may depend on the nature of the prepulse reaction is further discussed.

Control of limb movements may be impaired after stroke due to the loss of connectivity between the cerebral cortex and spinal cord. A notion to improve motor function in stroke survivors is to use alternate motor fibers, such as the reticulospinal tract (RST), which originate from the brainstem and terminate at different levels of spinal cord. One way of targeting the RST is to use a “StartReact” protocol to foster premature release of a preplanned movement in response to a startling stimulus. Our aim was to find support for the preservation of such StartReact effect in stroke survivors. We conducted a systematic review with meta-analysis of literature published in English up to September 2020, to explore differences in motor responses to startling stimuli in StartReact effects. Protocol of the study was registered (PROSPERO Registration No. CRD42020191581). PubMed, Google Scholar, Web of Science, PsycINFO, and Science Direct were searched for relevant literature. The meta-analysis contained six studies involving a total of 151 stroke and healthy participants. Muscle onset latency data were extracted from the qualifying studies and compared using RevMan. StartReact effect was present in both stroke and healthy groups, represented by shortened muscle onset latency when startling stimulus was present. There was considerable heterogeneity of the outcome measures, which was attributed to the range of motor impairments among stroke survivors and methodologies used. Our findings support the notion of preservation of preprogramming ability and suitability of RST and StartReact effect for motor rehabilitation following stroke.

Exposure to high ambient temperature is a stressor that influences both biological and behavioral functions and has been previously shown to have an extensive impact on brain structure and function. Physiological, cellular and behavioral responses to heat-stress (HS) (40–41 °C, 2 h) were evaluated in adult male Sprague-Dawley rats. The effect of HS exposure before predator-scent stress (PSS) exposure (i.e., HS preconditioning) was examined. Finally, a possible mechanism of HS-preconditioning to PSS was investigated. Immunohistochemical analyses of chosen cellular markers were performed in the hippocampus and in the hypothalamic paraventricular nucleus (PVN). Plasma corticosterone levels were evaluated, and the behavioral assessment included the elevated plus-maze (EPM) and the acoustic startle response (ASR) paradigms. Endogenous levels of heat shock protein (HSP)-70 were manipulated using an amino acid (L-glutamine) and a pharmacological agent (Doxazosin). A single exposure to an acute HS resulted in decreased body mass (BM), increased body temperature and increased corticosterone levels. Additionally, extensive cellular, but not behavioral changes were noted. HS-preconditioning provided behavioral resiliency to anxiety-like behavior associated with PSS, possibly through the induction of HSP-70. Targeting of HSP-70 is an attractive strategy for stress-related psychopathology treatment.

Prepulse inhibition (PPI) is a behavioural phenomenon in which a preceding weaker stimulus suppresses the startle response to a subsequent stimulus. The effect of PPI has been found to be reduced in psychiatric patients and is a promising neurophysiological indicator of psychiatric disorders. Because the neural circuit of the startle response has been identified at the cellular level, investigating the mechanism underlying PPI in Drosophila melanogaster larvae through experiment-based mathematical modelling can provide valuable insights. We recently identified PPI in Drosophila larvae and found that PPI was reduced in larvae mutated with the Centaurin gamma 1A (CenG1A) gene, which may be associated with autism. In this study, we used numerical simulations to investigate the neural mechanisms underlying PPI in Drosophila larvae. We adjusted the parameters of a previously developed Drosophila larvae computational model and demonstrated that the model could reproduce several behaviours, including PPI. An analysis of the temporal changes in neuronal activity when PPI occurs using our neural circuit model suggested that the activity of specific neurons triggered by prepulses has a considerable effect on PPI. Furthermore, we validated our speculations on PPI reduction in CenG1A mutants with simulations.