Ca2+-dependent activator protein for secretion 2 (CAPS2) regulates dense-core vesicle (DCV) exocytosis to facilitate peptidergic and catecholaminergic transmitter release. CAPS2 deficiency in mice has mild neuronal effects but markedly impairs social behavior. Rare de novo Caps2 alterations also occur in autism spectrum disorder, although whether CAPS2-mediated release influences social behavior remains unclear. Here, we demonstrate that CAPS2 is associated with DCV exocytosis-mediated release of the social interaction modulatory peptide oxytocin (OXT). CAPS2 is expressed in hypothalamic OXT neurons and localizes to OXT nerve projection and OXT release sites, such as the pituitary. Caps2 KO mice exhibited reduced plasma albeit increased hypothalamic and pituitary OXT levels, indicating insufficient release. OXT neuron-specific Caps2 conditional KO supported CAPS2 function in pituitary OXT release, also affording impaired social interaction and recognition behavior that could be ameliorated by exogenous OXT...

Binge-eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in fronto-striatal regions implicated in self-regulatory control, and an influential theory posits that binge-eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge-eating in underweight individuals (i.e., the anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (33 BN, 22 AN-BP, 30 controls). Participants underwent repeated functional MRI scanning, during performance of the stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses...

Pursuing rewards while avoiding danger is an essential function of any nervous system. Here, we examine a new mechanism helping rats negotiate the balance between risk and reward when making high-stakes decisions. Specifically, we focus on GABA neurons within an emerging mesolimbic circuit nexus—the ventral pallidum (VP). These neurons play a distinct role from other VP neurons in simple motivated behaviors in mice, but their roles in more complex motivated behaviors is unknown. Here, we interrogate the behavioral functions of VPGABA neurons in male and female transgenic GAD1:Cre rats (and wildtype littermates), using a reversible chemogenetic inhibition approach. Employing a behavioral assay of risky decision making, and of the food-seeking and shock-avoidance components of this task, we show that engaging inhibitory Gi/o signaling specifically in VPGABA neurons suppresses motivation to pursue highly salient palatable foods, and possibly also motivation to avoid being shocked. In contrast, inhibiting thes...

Deficits in impulse control and attention are prominent in the symptomatology of mental disorders such as ADHD, substance addiction, schizophrenia and bipolar disorder, yet the underlying mechanisms are incompletely understood. Frontostriatal structures, such as the nucleus accumbens (NAcb), the medial prefrontal cortex (mPFC), and their dopaminergic innervation from the ventral tegmental area (VTA) have been implicated in impulse control and attention. What remains unclear, is how the temporal pattern of activity of these VTA projections contributes to these processes. Here, we optogenetically stimulated VTA dopamine cells, as well as VTA projections to the nucleus accumbens core (NAcbC), shell (NAcbS) and the mPFC in male rats performing the 5-choice serial reaction time task. Our data show that stimulation of VTA DA neurons, and VTA projections to the NAcbC and the mPFC immediately prior to presentation of the stimulus cue, impaired attention but spared impulse control. Importantly, in addition to reduc...

GABAergic neurons are key circuit elements in cortical networks. In spite of growing evidence showing that inhibitory cells play a critical role in the lateral (LA) and basal (BA) amygdala functions, neither the number of GABAergic neurons nor the ratio of their distinct types have been determined in these amygdalar nuclei. Using unbiased stereology, we found that the ratio of GABAergic neurons in the BA (22%) is significantly higher than in the LA (16%) in both male and female mice. No difference was observed between the right and left hemispheres in either sexes. In addition, we assessed the ratio of the major inhibitory cell types in both amygdalar nuclei. Using transgenic mice and a viral strategy for visualizing inhibitory cells combined with immunocytochemistry, we estimated that the following cell types together compose the vast majority of GABAergic cells in the LA and BA: axo-axonic cells (5.5-6%), basket cells expressing parvalbumin (17-20%) or cholecystokinin (7-9%), dendrite-targeting inhibitor...

Diverse gene products contribute to the pathogenesis of Alzheimer’s disease (AD). Experimental models have helped elucidate their mechanisms and impact on brain functions. Human amyloid precursor protein (hAPP) transgenic mice from line J20 (hAPP-J20 mice) are widely used to simulate key aspects of AD. However, they also carry an insertional mutation in noncoding sequence of one Zbtb20 allele, a gene involved in neural development. We demonstrate that heterozygous hAPP-J20 mice have reduced Zbtb20 expression in some AD-relevant brain regions, but not others, and that Zbtb20 levels are higher in hAPP-J20 mice than heterozygous Zbtb20 knockout ( Zbtb20 +/–) mice. Whereas hAPP-J20 mice have premature mortality, severe deficits in learning and memory, other behavioral alterations, and prominent nonconvulsive epileptiform activity, Zbtb20 +/– mice do not. Thus, the insertional mutation in hAPP-J20 mice does not ablate the affected Zbtb20 allele and is unlikely to account for the AD-like phenotype of this model....

Among all voltage-gated potassium (Kv) channels, Kv2 channels are the most widely expressed in the mammalian brain. However, studying Kv2 in neurons has been challenging due to a lack of high-selective blockers. Recently, a peptide toxin, guangxitoxin-1E, has been identified as a specific inhibitor of Kv2, thus facilitating the study of Kv2 in neurons. The mammalian dorsal cochlear nucleus (DCN) integrates auditory and somatosensory information. In the DCN, cartwheel inhibitory interneurons receive excitatory synaptic inputs from parallel fibers conveying somatosensory information. The activation of parallel fibers drives action potentials in the cartwheel cells up to 130 Hz in vivo , and the excitation of cartwheel cells leads to the strong inhibition of principal cells. Therefore, cartwheel cells play crucial roles in monaural sound localization and cancelling detection of self-generated sounds. However, how Kv2 controls the high-frequency firing in cartwheel cells is unknown. In this study, we performed...

Our subjective perception of time is optimized to temporal regularities in the environment. This is illustrated by the central tendency effect: when estimating a range of intervals, short intervals are overestimated whereas long intervals are underestimated to reduce the overall estimation error. Most models of interval timing ascribe this effect to the weighting of the current interval with previous memory traces after the interval has been perceived. Alternatively, the perception of the duration could already be flexibly tuned to its temporal context. We investigated this hypothesis using an interval reproduction task in which human participants (both sexes) reproduced a shorter and longer interval range. As expected, reproductions were biased towards the subjective mean of each presented range. EEG analyses showed that temporal context indeed affected neural dynamics during the perception phase. Specifically, longer previous durations decreased CNV and P2 amplitude and increased beta power. In addition,...

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc , are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signalling. Here we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 usi...

Sleep shapes cortical network activity, fostering global homeostatic down-regulation of excitability while maintaining or even up-regulating excitability in selected networks in a manner that supports memory consolidation. Here we used two-photon calcium imaging of cortical layer 2/3 neurons in sleeping male mice to examine how these seemingly opposing dynamics are balanced in cortical networks. During slow-wave sleep (SWS) episodes, mean calcium activity of excitatory pyramidal (Pyr) cells decreased. Simultaneously, however, variance in Pyr population calcium activity increased, contradicting the notion of a homogenous down-regulation of network activity. Indeed, we identified a subpopulation of Pyr cells distinctly up-regulating calcium activity during SWS, which were highly active during sleep spindles known to support mnemonic processing. REM episodes following SWS were associated with a general down-regulation of Pyr cells - including the subpopulation of Pyr cells active during spindles - which persi...