Sensorimotor Gating Research Articles

Within-subjects vs between-subjects co-variation of prepulse-elicited reaction and the diminution of startle to the succeeding pulse stimulus in the prepulse inhibition paradigm

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.

Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls.Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.

Deletion of Schizophrenia Susceptibility Gene Ulk4 Leads to Abnormal Cognitive Behaviors via Akt-GSK-3 Signaling Pathway in Mice.

Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/β were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/β was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice.

Effects of Increasing Endocannabinoid 2‐AG Tone on Sensorimotor Gating and Anxiety‐like behavior

The cannabinoid system has been widely studied for its ability to modulate multiple behavioral functions, including addiction‐like behaviors. Our study aimed to determine if increasing endocannabinoid availability would alter sensorimotor gating and anxiety‐like behavior in rats. Both types of behavior are aberrant in psychiatric illnesses such as post‐traumatic stress disorder (PTSD). Sensorimotor gating is a mechanism which protects the brain from being overloaded by sensory stimuli to allow for normal information processing. The functionality of sensorimotor gating can be assessed using the prepulse inhibition (PPI) of startle paradigm, in which a weak prestimulus prior to a startling stimulus inhibits the resultant startle response. We were particularly interested in pursuing an understudied approach, augmentation of endogenous endocannabinoid ‘tone’ via inhibition of monoacylglycerol lipase (MAGL), the breakdown enzyme for the endocannabinoid 2‐AG. To inhibit MAGL, we administered the JZL184 to increase brain levels of 2‐AG. JZL184 did not affect PPI on its own but did reverse the PPI deficit that was produced by the psychotomimetic, amphetamine. Because JZL184 reversed sensorimotor gating deficits, we wanted to further determine if JZL184 possesses anxiety‐reducing effects. The elevated plus maze (EPM) assesses rats’ innate anxiety‐like state by measuring relative time spent exploring novel (fear‐inducing) spaces (the open arms of the EPM) versus remaining in spaces that feel ‘safe’ (the closed arms of the EPM, which are darker and enclosed by walls). While JZL184 (16 mg/kg) did not increase open arm entries or time, it did reduce time spent in the closed arms. Moreover, it increased center time (an intermediate space between the open and closed arms that is moderately fear‐inducing) and stretch‐attends (rats stretch their bodies so that their head can peer into the open arm while their hindpaws remain in a closed arm). Both of those measures are ethological indices of novel‐environment exploration. Taken together, these findings indicate that JZL184 produces a subtle anxiety‐reducing effect in the EPM. To our knowledge, we are the first to demonstrate this effect via ethological measures of EPM exploration. Similarly, our data are the first to show effects of JZL184 on PPI. These results raise the possibility that modulation of the endocannabinoid system, specifically 2‐AG tone, could be a novel pharmacological mechanism to regulate cognitive and emotional processes related to psychiatric disorders like PTSD.

Perceptual spatial position induces the attentional enhancement of prepulse inhibition and its neural mechanism

Prepulse inhibition (PPI) is a sensorimotor gating process that reduces the startling response when a weaker sensory stimulus precedes a sudden startling stimulus. Perceptual spatial separation (PSS) between the prepulse and the background noise was found to enhance PPI compared to perceptual spatial co-location (PSC). However, little is known about the perceptual characteristics of prepulses in the PSS that induce more inhibition of the startling response and the associated neural mechanism. The dorsocentral striatum (DCS) was the convergence of spatial information from the cortical and thalamic circuits. Our study investigated whether the perceptual spatial position of prepulses induced spatial attentional modulation of PPI. In addition, whether the DCS was involved in spatial attentional modulation's neural circuits of PPI. In our study, the relative perceptual image positions of the prepulse and masker were controlled by the playback time difference between the two loudspeakers, i.e., PSS and PSC. The specific spatial attention of the prepulse was conditioned by foot shock. The results revealed that PPI was generally enhanced after fear conditioning/conditioning-control manipulation across all rats. Further enhancement of PPI in the PSS condition occurred only in the fear conditioning position, not in the conditioning-control position. We first found that PPI did not show specific spatial enhancement in the drug-blocking bilateral DCS rats with 2 mM kynurenic acid. These results demonstrated that the perceptual spatial position modulated the spatial attention of prepulse and improved PPI. DCS was involved in the attentional modulation neural circuits of PPI and processed spatial information of prepulse.

Maternal immune activation accelerates puberty initiation and alters mechanical allodynia in male and female C57BL6/J mice.

The mechanisms that link maternal immune activation (MIA) with the onset of neurodevelopmental disorders remain largely unclear. Accelerated puberty is also associated with a heightened risk for psychopathology in later life, but there is a dearth of evidence on the impacts of maternal infection on pubertal timing. We examined the effects of MIA on reproductive development, mechanical allodynia, and sensorimotor gating in juvenile, adolescent, and adult male and female mice. Moreover, we investigated hypothalamic neural markers associated with the reproductive and stress axes. Finally, we tested the mitigating effects of environmental enrichment (EE), which has clinical relevancy in human rehabilitation settings. Our results show that administration of polyinosinic-polycytidylic acid (poly(I:C)) on gestational day 12.5 led to early preputial separation, vaginal openings, and age of first estrus in offspring. MIA exposure altered pain sensitivity across development and modestly altered prepulse inhibition. The downregulation of Nr3c1 and Oprk mRNA in the hypothalamus of juvenile mice suggests that MIA's effects may be mediated through disruption of hypothalamic-pituitary-adrenal axis activity. In contrast, life-long housing with EE rescued many of these MIA-induced consequences. Overall, our findings suggest that accelerated puberty may be associated with the deleterious effects of infection during pregnancy and the onset of psychopathology.

Combined prior chronic methamphetamine treatment and gp120 expression reduce PPI in aged male but not female mice

Methamphetamine (METH) use disorder is highly prevalent among people with HIV and is a significant public health problem. Furthermore, people with HIV are living longer and using drugs such as METH even into old age, making it important to understand the effects of METH use and aging in this population. HIV, METH, and aging negatively impact a variety of brain functions, including sensorimotor gating (i.e. - automatic, pre-conscious information processing). Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in animals, thereby allowing for preclinical studies. Little is known about how HIV, METH, and aging interact to affect PPI. The goal of this study was therefore to examine how METH affects PPI in aged gp120 mice, a mouse model of HIV. PPI was measured at 8, 14, and 22 months in male and female wild type (WT) and gp120 mice. PPI was also measured during and after METH treatment at 23–24 months. Aging was associated with decreased PPI in both sexes and genotypes. Combined prior METH treatment and gp120 expression caused the greatest reduction in PPI in aged male mice. Prior METH treatment decreased PPI in aged WT female mice, but not aged gp120 female mice. Overall, these results suggest the effects of HIV and METH on information processing seem to be influenced by age and sex. Combined HIV and METH may impair information processing in older men, but not older women.

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

PurposePrenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour.ProceduresPregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI).Results[18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits.ConclusionsOur results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.

The voltage-gated Ca2+ channel subunit α2δ-4 regulates locomotor behavior and sensorimotor gating in mice.

Voltage-gated Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in sensorimotor gating and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

Portable Neuroimaging-Guided Noninvasive Brain Stimulation of the Cortico-Cerebello-Thalamo-Cortical Loop-Hypothesis and Theory in Cannabis Use Disorder.

Background: Maladaptive neuroplasticity-related learned response in substance use disorder (SUD) can be ameliorated using noninvasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on a competing neurobehavioral decision systems model. The next objective was to develop the theory by conducting a computational simulation of NIBS of the cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD)-related dysfunctional “cue-reactivity”—a construct closely related to “craving”—that is a core symptom. Our third objective was to test the feasibility of a neuroimaging-guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG) metrics of sensorimotor gating. Therefore, we conducted a computational simulation of NIBS, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) of the cerebellar cortex and deep cerebellar nuclei (DCN) of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging-guided NIBS approach for the cerebellar lobule (VII) and prefrontal cortex based on a healthy human study. Results: Simulation of cerebellar tDCS induced gamma oscillations in the cerebral cortex, while transcranial temporal interference stimulation induced a gamma-to-beta frequency shift. A preliminary healthy human study (N = 10) found that 2 mA cerebellar tDCS evoked similar oxyhemoglobin (HbO) response in the range of 5 × 10−6 M across the cerebellum and PFC brain regions (α = 0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO-driven phase–amplitude-coupled (PAC; 4 Hz, ±2 mA (max)) cerebellar tACS evoked HbO levels in the range of 10−7 M that were statistically different (α = 0.01) across these brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC and closed-loop fNIRS-driven ctACS at 4 Hz, which may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging for closed-loop NIBS during operant conditioning.

A mutant allele of glycoprotein M6-B (Gpm6b) facilitates behavioral flexibility but increases delay discounting.

The neuronal membrane glycoprotein M6B (Gpm6b) gene encodes a membrane glycoprotein that belongs to the proteolipid protein family, and is enriched in neurons, oligodendrocytes, and subset of astrocytes in the central nervous system. GPM6B is thought to play a role in neuronal differentiation, myelination, and inactivation of the serotonin transporter via internalization. Recent human genome-wide association studies (GWAS) have implicated membrane glycoproteins (both GPM6B and GPM6A) in the regulation of traits relevant to psychiatric disorders, including neuroticism, depressed affect, and delay discounting. Mouse studies have implicated Gpm6b in sensorimotor gating and regulation of serotonergic signaling. We used CRISPR to create a mutant Glycoprotein M6B (Gpm6b) allele on a C57BL/6J mouse background. Because Gpm6b is located on the X chromosome, we focused on male Gpm6b mutant mice and their wild-type littermates (WT) in two behavioral tests that measured aspects of impulsive or flexible decision-making. We found that Gpm6b deletion caused deficits in a delay discounting task. In contrast, reward sensitivity was enhanced thereby facilitating behavioral flexibility and improving performance in the probabilistic reversal learning task. Taken together these data further delineate the role of Gpm6b in decision making behaviors that are relevant to multiple psychiatric disorders.

Post-synaptic scaffold protein TANC2 in psychiatric and somatic disease risk.

ABSTRACTUnderstanding the shared genetic aetiology of psychiatric and medical comorbidity in neurodevelopmental disorders (NDDs) could improve patient diagnosis, stratification and treatment options. Rare tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 (TANC2)-disrupting variants were disease causing in NDD patients. The post-synaptic scaffold protein TANC2 is essential for dendrite formation in synaptic plasticity and plays an unclarified but critical role in development. We here report a novel homozygous-viable Tanc2-disrupted function model in which mutant mice were hyperactive and had impaired sensorimotor gating consistent with NDD patient psychiatric endophenotypes. Yet, a multi-systemic analysis revealed the pleiotropic effects of Tanc2 outside the brain, such as growth failure and hepatocellular damage. This was associated with aberrant liver function including altered hepatocellular metabolism. Integrative analysis indicates that these disrupted Tanc2 systemic effects relate to interaction with Hippo developmental signalling pathway proteins and will increase the risk for comorbid somatic disease. This highlights how NDD gene pleiotropy can augment medical comorbidity susceptibility, underscoring the benefit of holistic NDD patient diagnosis and treatment for which large-scale preclinical functional genomics can provide complementary pleiotropic gene function information.

Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Transgenerational Sex-dependent Disruption of Dopamine Function Induced by Maternal Immune Activation.

Several epidemiological studies suggest an association between maternal infections during pregnancy and the emergence of neurodevelopmental disorders in the offspring, such as autism and schizophrenia. Animal models broadened the knowledge about the pathophysiological mechanisms that develop from prenatal infection to the onset of psychopathological phenotype. Mounting evidence supports the hypothesis that detrimental effects of maternal immune activation might be transmitted across generations. Here, we explored the transgenerational effects on the dopamine system of a maternal immune activation model based on the viral mimetic polyriboinosinic-polyribocytidilic acid. We assessed dopamine neurons activity in the ventral tegmental area by in vivo electrophysiology. Furthermore, we studied two behavioral tests strictly modulated by the mesolimbic dopamine system, i.e., the open field in response to amphetamine and the prepulse inhibition of the startle reflex in response to the D2 agonist apomorphine. Second-generation adult male rats did not display any deficit in sensorimotor gating; however, they displayed an altered activity of ventral tegmental area dopamine neurons, indexed by a reduced spontaneous firing rate and a heightened motor activation in response to amphetamine administration in the open field. On the other hand, second-generation female rats were protected from ancestors’ polyriboinosinic-polyribocytidilic acid treatment, as they did not show any alteration in dopamine cell activity or in behavioral tests. These results confirm that maternal immune activation negatively influences, in a sex-dependent manner, neurodevelopmental trajectories of the dopamine system across generations.

Research Progress in the Study of Startle Reflex to Disease States.

The startle reflex is considered a primitive physiological reflex, a defense response that occurs in the organism when the body feels sudden danger and uneasiness, characterized by habituation and sensitization effects, and studies on the startle reflex often deal with pre-pulse inhibition (PPI) and sensorimotor gating. Under physiological conditions, the startle reflex is stable at a certain level, and when the organism is in a pathological state, such as stroke, spinal cord injury, schizophrenia, and other diseases, the reflex undergoes a series of changes, making it closely related to the progress of disease. This paper summarizes the startle reflex in physiological and pathological states by reviewing the databases of PubMed, Web of Science, Cochrane Library, EMBASE, China Biology Medicine, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, Wanfang Data, and identifies and analyzes the startle reflex and excessive startle reaction disorder.

Female-specific role of ciliary neurotrophic factor in the medial amygdala in promoting stress responses

Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF−/− littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF−/− mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.

Orexin deficiency affects sensorimotor gating and its amphetamine-induced impairment

The orexin neuropeptides have an important role in the regulation of the sleep/wake cycle and foraging, as well as in reward processing and emotions. Furthermore, recent research implicates the orexin system in different behavioral endophenotypes of neuropsychiatric diseases such as social avoidance and cognitive flexibility. Utilizing orexin-deficient mice, the present study tested the hypothesis that orexin is involved in two further mouse behavioral endophenotypes of neuropsychiatric disorders, i.e., sensorimotor gating and amphetamine sensitivity. The data revealed that orexin-deficient mice expressed a deficit in sensorimotor gating, measured by prepulse inhibition of the startle response. Amphetamine treatment impaired prepulse inhibition in wildtype and heterozygous orexin-deficient mice, but had no effects in homozygous orexin-deficient mice. Furthermore, locomotor activity and center time in the open field was not affected by orexin deficiency but was similarly increased or decreased, respectively, by amphetamine treatment in all genotypes. These data indicate that the orexin system modulates prepulse inhibition and is involved in mediating amphetamine's effect on prepulse inhibition. Future studies should investigate whether pharmacological manipulations of the orexin system can be used to treat neuropsychiatric diseases associated with deficits in sensorimotor gating, such as schizophrenia or attention deficit hyperactivity disorder.

Effects of Prenatal Nicotine, THC, or Co-Exposure on Cognitive Behaviors in Adolescent Male and Female Rats.

Although there has been a decrease in the prevalence of tobacco smoking, exposure to nicotine during pregnancy remains a substantial problem worldwide. Further, given the recent escalation in e-cigarette use and legalization of cannabis, it has become essential to understand the effects of nicotine and cannabinoid co-exposure during early developmental stages. We systematically examined the effects of nicotine and/or THC prenatal exposure on cognitive behaviors in male and female offspring. Dams were exposed to nicotine vape or vehicle, and oral edible THC or vehicle, throughout pregnancy. Adolescent offspring were then tested in the prepulse inhibition test, novel object recognition task, and novelty suppressed feeding task. At birth, pups from mothers exposed to nicotine vape or oral THC exhibited reduced body weight, compared to control pups. Prenatal nicotine vape exposure resulted in a decreased baseline startle reactivity in adolescent male and female rats, and in females, enhanced sensorimotor gating in the prepulse inhibition test. Prenatal nicotine and THC co-exposure resulted in significant deficits in the prepulse inhibition test in males. Deficits in short-term memory were also found in males prenatally exposed to THC, either alone or with nicotine co-exposure, and in females exposed to THC alone. Finally, in males, a modest increase in anxiety-associated behaviors was found with THC or nicotine exposure in the latency to approach a novel palatable food. These studies demonstrate differential effects of prenatal exposure to e-cigarette nicotine vape and/or edible THC on cognitive function, with differing effects within male and female groups. These studies demonstrate an impact of nicotine, THC, or co-exposure during early developmental stages in utero on behavioral outcomes in adolescence. These findings have important translational implications given the continued use of nicotine and THC containing products by pregnant women worldwide, which can be applied to support healthcare and policy efforts restricting nicotine and THC use during pregnancy.

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder.

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD‐93 protein reduction) a novel clinically relevant Dlg2 +/− rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N‐Methyl‐D‐aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD‐93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 +/− rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 +/− mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.

Pten haploinsufficiency causes desynchronized growth of brain areas involved in sensory processing

SummaryHow changes in brain scaling relate to altered behavior is an important question in neurodevelopmental disorder research. Mice with germline Pten haploinsufficiency (Pten+/-) closely mirror the abnormal brain scaling and behavioral deficits seen in humans with macrocephaly/autism syndrome, which is caused by PTEN mutations. We explored whether deviation from normal patterns of growth can predict behavioral abnormalities. Brain regions associated with sensory processing (e.g., pons and inferior colliculus) had the biggest deviations from expected volume. While Pten+/- mice showed little or no abnormal behavior on most assays, both sexes showed sensory deficits, including impaired sensorimotor gating and hyporeactivity to high-intensity stimuli. Developmental analysis of this phenotype showed sexual dimorphism for hyporeactivity. Mapping behavioral phenotypes of Pten+/- mice onto relevant brain regions suggested abnormal behavior is likely when associated with relatively enlarged brain regions, while unchanged or relatively decreased brain regions have little predictive value.