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Background Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD). Carriers of this deletion show divergent symptoms besides the core features of autism spectrum disorder, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. Methods We used mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) and their sex-matched wild-type littermates for the study and examined their anxiety-related behaviors, auditory perception, and central amygdala circuit function using behavioral, circuit tracing, and electrophysiological techniques. Results Mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) had sex-specific anxiety-related behavioral and neural circuit changes. Specifically, we found that female, but not male, 16p11.2 del/+ mice showed enhanced fear generalization—a hallmark of anxiety disorders—after auditory fear conditioning and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male, 16p11.2 del/+ mice. Conclusions Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.

The ventral pallidum (VP) is critical for invigorating reward seeking and is also involved in punishment avoidance, but how it contributes to such opposing behavioural actions remains unclear. Here we show that GABAergic and glutamatergic VP neurons selectively control behaviour in opposing motivational contexts. In vivo recording combined with optogenetics in mice revealed that these two populations oppositely encode positive and negative motivational value, are differentially modulated by animal’s internal state and determine the behavioural response during motivational conflict. Furthermore, GABAergic VP neurons are essential for movements towards reward in a positive motivational context, but suppress movements in an aversive context. In contrast, glutamatergic VP neurons are essential for movements to avoid a threat but suppress movements in an appetitive context. Our results indicate that GABAergic and glutamatergic VP neurons encode the drive for approach and avoidance, respectively, with the balance between their activities determining the type of motivational behaviour.

Chromatin accessibility provides an important window into the regulation of gene expression. Recently, the Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) was developed to profile genome-wide chromatin accessibility. In this work we analyzed 193 ATAC-seq samples from 12 studies to determine the robustness of peaks, as well as their specificity across studies. We employ a read-downsampling approach and find that even samples which have high average read-depth yield poorly powered peaks using conventional pipelines. Finding that many peaks are sensitive to slight perturbations in read-sampling, we develop an approach to improve the robustness of peak signals and apply this novel method to detect differential accessibility between the amygdala and cortex. Most peak calling results heavily and unreasonably depend on the absolute number of reads, easily yielding artifacts when differential peak evaluations are performed. These problems can be ameliorated by resampling reads to determine the robust aggregate result.

SUMMARYBoth the lateral and the central nuclei of the amygdala are required for adaptive behavioral responses to environmental cues predicting threats. While experience-driven synaptic plasticity in the lateral amygdala is thought to underlie the formation of association between a sensory stimulus and an ensuing threat, how the central amygdala participates in such learning process remains unclear. Here we show that a specific class of central amygdala neurons, the protein kinase C-δ-expressing neurons, is essential for the synaptic plasticity underlying learning in the lateral amygdala, as it is required for lateral amygdala neurons to respond to unconditioned stimulus, and furthermore carries information about the unconditioned stimulus to instruct learning. Our results uncover an amygdala functional organization that may play a key role in diverse learning processes.

Experience-driven synaptic plasticity in the lateral amygdala is thought to underlie the formation of associations between sensory stimuli and an ensuing threat. However, how the central amygdala participates in such a learning process remains unclear. Here we show that PKC-δ-expressing central amygdala neurons are essential for the synaptic plasticity underlying learning in the lateral amygdala, as they convey information about the unconditioned stimulus to lateral amygdala neurons during fear conditioning.

Selective processing of behaviorally relevant sensory inputs against irrelevant ones is a fundamental cognitive function whose impairment has been implicated in major psychiatric disorders. It is known that the thalamic reticular nucleus (TRN) gates sensory information en route to the cortex, but the underlying mechanisms remain unclear. Here we show in mice that deficiency of the Erbb4 gene in somatostatin-expressing TRN neurons markedly alters behaviors that are dependent on sensory selection. Whereas the performance of the Erbb4-deficient mice in identifying targets from distractors was improved, their ability to switch attention between conflicting sensory cues was impaired. These behavioral changes were mediated by an enhanced cortical drive onto the TRN that promotes the TRN-mediated cortical feedback inhibition of thalamic neurons. Our results uncover a previously unknown role of ErbB4 in regulating cortico-TRN-thalamic circuit function. We propose that ErbB4 sets the sensitivity of the TRN to cortical inputs at levels that can support sensory selection while allowing behavioral flexibility.

The basal ganglia, a group of subcortical nuclei, play a crucial role in decision making by selecting actions and evaluating their outcomes1,2. While much is known about the function of the basal ganglia circuitry in selection1,3,4, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We found in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision making task. Moreover, cell-type-specific synaptic manipulations revealed that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies virus-assisted monosynaptic tracing5, we discovered that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the “limbic” regions of the subthalamic nucleus (STN). Our results provide the first direct evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus where information of opposing valence is integrated to determine whether action outcomes are better or worse than expected.

Transforming Growth Factor beta (Tgfbeta) and associated signaling effectors are expressed in the forebrain, but little is known about the role of this multifunctional cytokine during forebrain development. Using hippocampal and cortical primary cell cultures of developing mouse brains, this study identified Tgfbeta-regulated genes not only associated with cell cycle exit of progenitors but also with adoption of neuronal cell fate. Accordingly, we observed not only an antimitotic effect of Tgfbeta on progenitors but also an increased expression of neuronal markers in Tgfbeta treated cultures. This effect was dependent upon Smad4. Furthermore, in vivo loss-of-function analyses using Tgfbeta2(-/-)/Tgfbeta3(-/-) double mutant mice showed the opposite effect of increased cell proliferation and fewer neurons in the cerebral cortex and hippocampus. Gata2, Runx1, and Nedd9 were candidate genes regulated by Tgfbeta and known to be involved in developmental processes of neuronal progenitors. Using siRNA-mediated knockdown, we identified Nedd9 as an essential signaling component for the Tgfbeta-dependent increase in neuronal cell fate. Expression of this scaffolding protein, which is mainly described as a signaling molecule of the beta1-integrin pathway, was not only induced after Tgfbeta treatment but was also associated with morphological changes of the Nestin-positive progenitor pool observed upon exposure to Tgfbeta.