Functional Ontogeny of Hypothalamic Agrp Neurons in Neonatal Mouse Behaviors.

Hypothalamic Agrp neurons regulate food ingestion in adult mice. Whether these neurons are functional before animals start to ingest food is unknown. Here, we studied the functional ontogeny of Agrp neurons during breastfeeding using postnatal day 10 mice. In contrast to adult mice, we show that isolation from the nursing nest, not milk deprivation or ingestion, activated Agrp neurons. Non-nutritive suckling and warm temperatures blunted this effect. Using in vivo fiber photometry, neonatal Agrp neurons showed a rapid increase in activity upon isolation from the nest, an effect rapidly diminished following reunion with littermates. Neonates unable to release GABA from Agrp neurons expressed blunted emission of isolation-induced ultrasonic vocalizations. Chemogenetic overactivation of these neurons further increased emission of these ultrasonic vocalizations, but not milk ingestion. We uncovered important functional properties of hypothalamic Agrp neurons during mouse development, suggesting these neurons facilitate offspring-to-caregiver bonding.

Functional specialization and distributed processing across marmoset lateral prefrontal subregions.

A prominent aspect of primate lateral prefrontal cortex organization is its division into several cytoarchitecturally distinct subregions. Neurophysiological investigations in macaques have provided evidence for the functional specialization of these subregions, but an understanding of the relative representational topography of sensory, social, and cognitive processes within them remains elusive. One explanatory factor is that evidence for functional specialization has been compiled largely from a patchwork of findings across studies, in many animals, and with considerable variation in stimulus sets and tasks. Here, we addressed this by leveraging the common marmoset (Callithrix jacchus) to carry out large-scale neurophysiological mapping of the lateral prefrontal cortex using high-density microelectrode arrays, and a diverse suite of test stimuli including faces, marmoset calls, and spatial working memory task. Task-modulated units and units responsive to visual and auditory stimuli were distributed throughout the lateral prefrontal cortex, while those with saccade-related activity or face-selective responses were restricted to 8aV, 8aD, 10, 46 V, and 47. Neurons with contralateral visual receptive fields were limited to areas 8aV and 8aD. These data reveal a mixed pattern of functional specialization in the lateral prefrontal cortex, in which responses to some stimuli and tasks are distributed broadly across lateral prefrontal cortex subregions, while others are more limited in their representation.

Prenatal treatment with preimplantation factor improves early postnatal neurogenesis and cognitive impairments in a mouse model of Down syndrome.

Down syndrome (DS) is a genetic disease characterized by a supernumerary chromosome 21. Intellectual deficiency (ID) is one of the most prominent features of DS. Central nervous system defects lead to learning disabilities, motor and language delays, and memory impairments. At present, a prenatal treatment for the ID in DS is lacking. Subcutaneous administration of synthetic preimplantation factor (sPIF, a peptide with a range of biological functions) in a model of severe brain damage has shown neuroprotective and anti-inflammatory properties by directly targeting neurons and microglia. Here, we evaluated the effect of PIF administration during gestation and until weaning on Dp(16)1Yey mice (a mouse model of DS). Possible effects at the juvenile stage were assessed using behavioral tests and molecular and histological analyses of the brain. To test the influence of perinatal sPIF treatment at the adult stage, hippocampus-dependent memory was evaluated on postnatal day 90. Dp(16)1Yey pups showed significant behavioral impairment, with impaired neurogenesis, microglial cell activation and a low microglial cell count, and the deregulated expression of genes linked to neuroinflammation and cell cycle regulation. Treatment with sPIF restored early postnatal hippocampal neurogenesis, with beneficial effects on astrocytes, microglia, inflammation, and cell cycle markers. Moreover, treatment with sPIF restored the level of DYRK1A, a protein that is involved in cognitive impairments in DS. In line with the beneficial effects on neurogenesis, perinatal treatment with sPIF was associated with an improvement in working memory in adult Dp(16)1Yey mice. Perinatal treatment with sPIF might be an option for mitigating cognitive impairments in people with DS.

Bidirectional generative adversarial representation learning for natural stimulus synthesis.

Thousands of species use vocal signals to communicate with one another. Vocalizations carry rich information, yet characterizing and analyzing these complex, high-dimensional signals is difficult and prone to human bias. Moreover, animal vocalizations are ethologically relevant stimuli whose representation by auditory neurons is an important subject of research in sensory neuroscience. A method that can efficiently generate naturalistic vocalization waveforms would offer an unlimited supply of stimuli with which to probe neuronal computations. Although unsupervised learning methods allow for the projection of vocalizations into low-dimensional latent spaces learned from the waveforms themselves, and generative modeling allows for the synthesis of novel vocalizations for use in downstream tasks, we are not aware of any model that combines these tasks to synthesize naturalistic vocalizations in the waveform domain for stimulus playback. In this paper, we demonstrate BiWaveGAN: a bidirectional generative adversarial network (GAN) capable of learning a latent representation of ultrasonic vocalizations (USVs) from mice. We show that BiWaveGAN can be used to generate, and interpolate between, realistic vocalization waveforms. We then use these synthesized stimuli along with natural USVs to probe the sensory input space of mouse auditory cortical neurons. We show that stimuli generated from our method evoke neuronal responses as effectively as real vocalizations, and produce receptive fields with the same predictive power. BiWaveGAN is not restricted to mouse USVs but can be used to synthesize naturalistic vocalizations of any animal species and interpolate between vocalizations of the same or different species, which could be useful for probing categorical boundaries in representations of ethologically relevant auditory signals.NEW & NOTEWORTHY A new type of artificial neural network is presented that can be used to generate animal vocalization waveforms and interpolate between them to create new vocalizations. We find that our synthetic naturalistic stimuli drive auditory cortical neurons in the mouse equally well and produce receptive field features with the same predictive power as those obtained with natural mouse vocalizations, confirming the quality of the stimuli produced by the neural network.

Exploring ultrasonic communication in mice treated with Cannabis sativa oil: Audio data processing and correlation study with different behaviours.

Studying ultrasonic vocalizations (USVs) plays a crucial role in understanding animal communication, particularly in the field of ethology and neuropharmacology. Communication is associated with social behaviour; so, USVs study is a valid assay in behavioural readout and monitoring in this context. This paper delved into an investigation of ultrasonic communication in mice treated with Cannabis sativa oil (CS mice), which has been demonstrated having a prosocial effect on behaviour of mice, versus control mice (vehicle-treated, VH mice). To conduct this study, we created a dataset by recording audio-video files and annotating the duration of time that test mice spent engaging in social activities, along with categorizing the types of emitted USVs. The analysis encompassed the frequency of individual sounds as well as more complex sequences of consecutive syllables (patterns). The primary goal was to examine the extent and nature of diversity in ultrasonic communication patterns emitted by these two groups of mice. As a result, we observed statistically significant differences for each considered pattern length between the two groups of mice. Additionally, the study extended its research by considering specific behaviours, aiming to ascertain whether dissimilarities in ultrasonic communication between CS and VH mice are more pronounced or subtle within distinct behavioural contexts. Our findings suggest that while there is variation in USV communication between the two groups of mice, the degree of this diversity may vary depending on the specific behaviour being observed.

Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.

BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.

Context or arousal? Function of drumming in Mongolian gerbils (Meriones unguiculatus).

Drumming is a non-vocal auditory display producing airborne as well as seismic vibrations by tapping body extremities on a surface. It is mostly described as an alarm signal but is also discussed to signal dominance or mating quality. To clarify the function of drumming in Mongolian gerbils (Meriones unguiculatus), we compared the occurrence of drumming during predator, opposite-sex and same-sex encounters. We tested 48 captive Mongolian gerbils (Meriones unguiculatus) in three experiments. In predator experiments, subjects were exposed alone or with their cagemate to aerial and terrestrial predator dummies. In social encounter experiments, familiar and unfamiliar male-female dyads and same-sex dyads were confronted. For the same-sex encounters, a dominance index was calculated for each subject based on the number of won and lost conflicts. Drumming and drumming-call combinations were counted, and a multi-parametric sound analysis was performed. In all experiments drumming and drumming-call combinations occurred. In predator experiments, more subjects drummed when confronted with the predator stimulus than in the habituation phase. In social encounter experiments, more subjects drummed when facing an unfamiliar than a familiar conspecific. In addition, the accompanying call type and body posture of the sender differed between experiments. Thus, we suggest that whereas drumming signals an increased arousal state of the sender, the accompanying call type and the body posture signal context specific information.

Social and emotional alterations in mice lacking the short dystrophin-gene product, Dp71.

BACKGROUND: The Duchenne and Becker muscular dystrophies (DMD, BMD) are neuromuscular disorders commonly associated with diverse cognitive and behavioral comorbidities. Genotype-phenotype studies suggest that severity and risk of central defects in DMD patients increase with cumulative loss of different dystrophins produced in CNS from independent promoters of the DMD gene. Mutations affecting all dystrophins are nevertheless rare and therefore the clinical evidence on the contribution of the shortest Dp71 isoform to cognitive and behavioral dysfunctions is limited. In this study, we evaluated social, emotional and locomotor functions, and fear-related learning in the Dp71-null mouse model specifically lacking this short dystrophin. RESULTS: We demonstrate the presence of abnormal social behavior and ultrasonic vocalization in Dp71-null mice, accompanied by slight changes in exploratory activity and anxiety-related behaviors, in the absence of myopathy and alterations of learning and memory of aversive cue-outcome associations. CONCLUSIONS: These results support the hypothesis that distal DMD gene mutations affecting Dp71 may contribute to the emergence of social and emotional problems that may relate to the autistic traits and executive dysfunctions reported in DMD. The present alterations in Dp71-null mice may possibly add to the subtle social behavior problems previously associated with the loss of the Dp427 dystrophin, in line with the current hypothesis that risk and severity of behavioral problems in patients increase with cumulative loss of several brain dystrophin isoforms.

Noise intensity modulates the responses of mantled howler monkeys to anthropophony.

Anthropogenic noise is a major global pollutant but its effects on primates are poorly understood, limiting our ability to develop mitigation actions that favor their welfare and conservation. In this study, we used an experimental approach to determine the impact of variation in noise intensity on mantled howler monkeys (Alouatta palliata). We conducted the study at Los Tuxtlas (México), where we studied the physiological stress (proxied via fecal glucocorticoid metabolites, fGCM) and behavioral responses of 16 males. We played back chainsaw noise at two intensities (40 and 80 dB) and used days in which groups were not exposed to noise as matched controls. With increased noise intensity fGCM increased, vigilance and vocalizations were longer, and vigilance, vocalizations, and flight occurred quicker. Physiological and behavioral responses occurred even after low-intensity noise playbacks (i.e., 40 dB). Therefore, noise intensity is a significant factor explaining the responses of mantled howler monkeys to anthropogenic noise. These results imply that management actions aimed at eradicating anthropogenic noise are required for the conservation and welfare of mantled howler monkeys at Los Tuxtlas.

Agomelatine Is Unable to Attenuate Kainic Acid-Induced Deficits in Early Life Communicative Behavior.

Early life seizures are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments. Agomelatine is a melatonin agonist that effectively reduces behavioral comorbidities of seizures in adults; however, its ability to attenuate seizure-induced communicative deficits in neonates is unknown. To address this, we administered C57 mice either saline or kainic acid (KA) on postnatal day (PD) 10. The mice then received either agomelatine or saline 1-h post-status epilepticus. On PD 11, we assessed the quantity of USVs produced, the duration, peak frequency, fundamental frequency, and amplitude of the vocalizations, as well as the call type utilization. We found that KA increased vocal production and reduced USV variability relative to controls. KA also increased USV duration and amplitude and significantly altered the types of calls produced. Agomelatine did not attenuate any of the deficits. Our study is the first to assess agomelatine's efficacy to correct USVs and thus provides an important point of context to the literature, indicating that despite its high therapeutic efficacy to attenuate other behavioral comorbidities of seizures, agomelatine's ability to correct neonatal communicative deficits is limited.

Comparative Study of the Anxiolytic Activity of Songorine in Elevated Plus Maze Test and by Recording Ultrasonic Vocalizations.

It was found that the diterpene alkaloid songorine administered per os to mice at a dose of 25 µg/kg provides a pronounced anxiolytic effect during elevated plus maze testing comparable to the effect of the benzodiazepine anxiolytic phenazepam. Recording of ultrasonic vocalizations of animals revealed an increase in the number of short high-frequency (50 kHz) signals under the action of songorine and the reference drug, which confirms their anti-anxiety properties.

Composite receptive fields in the mouse auditory cortex.

A central question in sensory neuroscience is how neurons represent complex natural stimuli. This process involves multiple steps of feature extraction to obtain a condensed, categorical representation useful for classification and behaviour. It has previously been shown that central auditory neurons in the starling have composite receptive fields composed of multiple features. Whether this property is an idiosyncratic characteristic of songbirds, a group of highly specialized vocal learners or a generic property of sensory processing is unknown. To address this question, we have recorded responses from auditory cortical neurons in mice, and characterized their receptive fields using mouse ultrasonic vocalizations (USVs) as a natural and ethologically relevant stimulus and pitch-shifted starling songs as a natural but ethologically irrelevant control stimulus. We have found that these neurons display composite receptive fields with multiple excitatory and inhibitory subunits. Moreover, this was the case with either the conspecific or the heterospecific vocalizations. We then trained the sparse filtering algorithm on both classes of natural stimuli to obtain statistically optimal features, and compared the natural and artificial features using UMAP, a dimensionality-reduction algorithm previously used to analyse mouse USVs and birdsongs. We have found that the receptive-field features obtained with both types of the natural stimuli clustered together, as did the sparse-filtering features. However, the natural and artificial receptive-field features clustered mostly separately. Based on these results, our general conclusion is that composite receptive fields are not a unique characteristic of specialized vocal learners but are likely a generic property of central auditory systems. KEY POINTS: Auditory cortical neurons in the mouse have composite receptive fields with several excitatory and inhibitory features. Receptive-field features capture temporal and spectral modulations of natural stimuli. Ethological relevance of the stimulus affects the estimation of receptive-field dimensionality.

Hippocampus Modulates Vocalizations Responses at Early Auditory Centers.

Despite its prominence in learning and memory, hippocampal influence in early auditory processing centers remains unknown. Here, we examined how hippocampal activity modulates sound-evoked responses in the auditory midbrain and thalamus using optogenetics and functional MRI (fMRI) in rodents. Ventral hippocampus (vHP) excitatory neuron stimulation at 5 Hz evoked robust hippocampal activity that propagates to the primary auditory cortex. We then tested 5 Hz vHP stimulation paired with either natural vocalizations or artificial/noise acoustic stimuli. vHP stimulation enhanced auditory responses to vocalizations (with a negative or positive valence) in the inferior colliculus, medial geniculate body, and auditory cortex, but not to their temporally reversed counterparts (artificial sounds) or broadband noise. Meanwhile, pharmacological vHP inactivation diminished response selectivity to vocalizations. These results directly reveal the large-scale hippocampal participation in natural sound processing at early centers of the ascending auditory pathway. They expand our present understanding of hippocampus in global auditory networks.

Intracellular recordings reveal integrative function of the basolateral amygdala in acoustic communication.

The amygdala, a brain center of emotional expression, contributes to appropriate behavior responses during acoustic communication. In support of that role, the basolateral amygdala (BLA) analyzes the meaning of vocalizations through the integration of multiple acoustic inputs with information from other senses and an animal's internal state. The mechanisms underlying this integration are poorly understood. This study focuses on the integration of vocalization-related inputs to the BLA from auditory centers during this processing. We used intracellular recordings of BLA neurons in unanesthetized big brown bats that rely heavily on a complex vocal repertoire during social interactions. Postsynaptic and spiking responses of BLA neurons were recorded to three vocal sequences that are closely related to distinct behaviors (appeasement, low-level aggression, and high-level aggression) and have different emotional valence. Our novel findings are that most BLA neurons showed postsynaptic responses to one or more vocalizations (31 of 46) but that many fewer neurons showed spiking responses (8 of 46). The spiking responses were more selective than postsynaptic potential (PSP) responses. Furthermore, vocal stimuli associated with either positive or negative valence were similarly effective in eliciting excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs), and spiking responses. This indicates that BLA neurons process both positive- and negative-valence vocal stimuli. The greater selectivity of spiking responses than PSP responses suggests an integrative role for processing within the BLA to enhance response specificity in acoustic communication.NEW & NOTEWORTHY The amygdala plays an important role in social communication by sound, but little is known about how it integrates diverse auditory inputs to form selective responses to social vocalizations. We show that BLA neurons receive inputs that are responsive to both negative- and positive-affect vocalizations but their spiking outputs are fewer and highly selective for vocalization type. Our work demonstrates that BLA neurons perform an integrative function in shaping appropriate behavioral responses to social vocalizations.

Crocodile perception of distress in hominid baby cries.

It is generally argued that distress vocalizations, a common modality for alerting conspecifics across a wide range of terrestrial vertebrates, share acoustic features that allow heterospecific communication. Yet studies suggest that the acoustic traits used to decode distress may vary between species, leading to decoding errors. Here we found through playback experiments that Nile crocodiles are attracted to infant hominid cries (bonobo, chimpanzee and human), and that the intensity of crocodile response depends critically on a set of specific acoustic features (mainly deterministic chaos, harmonicity and spectral prominences). Our results suggest that crocodiles are sensitive to the degree of distress encoded in the vocalizations of phylogenetically very distant vertebrates. A comparison of these results with those obtained with human subjects confronted with the same stimuli further indicates that crocodiles and humans use different acoustic criteria to assess the distress encoded in infant cries. Interestingly, the acoustic features driving crocodile reaction are likely to be more reliable markers of distress than those used by humans. These results highlight that the acoustic features encoding information in vertebrate sound signals are not necessarily identical across species.

Environmental exposure to chlorpyrifos during gestation, APOE polymorphism and the risk on autistic-like behaviors.

Autism spectrum disorder (ASD) encompasses several neurodevelopmental conditions characterized by communication and social impairment, as well as repetitive patterns of behavior. However, it can co-occur with other mental conditions such as anxiety. The massive use of chlorpyrifos (CPF) has been linked to the increased prevalence of developmental disorders. Likewise, ASD has also been closely linked to a wide variety of genetic factors. The aims of the present investigation are to study how gestational CPF exposure and APOE polymorphism affects communication skills, early development and mid-term anxiety-like behaviors, as well as, changes in gene expression related to the cholinergic system. C57BL/6J and humanized apoE3 and apoE4 homozygous mice were exposed to 0 or 1 mg/kg/day of CPF through the diet, from gestational day (GD) 12-18. In addition, a group of C57BL/6J females were injected subcutaneously with 300 mg/kg/day of valproic acid (VPA) on GD 12 and 13. This group was used as a positive control for studying some core and associated autism-like behaviors. Communication skills by means of ultrasonic vocalizations and physical/motor development were assessed during the preweaning period, whereas locomotor activity, anxiety-like behaviors and the gene expression of cholinergic elements were evaluated during adolescence. Our results showed that C57BL/6J mice prenatally exposed to CPF or VPA showed a decrease in body weight and a delay in eye opening. Communication and anxiety behavior were affected differently depending on treatment, while gene expression was altered by sex and treatment. In addition, none of the parameters evaluated in apoE transgenic mice exposed to CPF were affected, but there were differences between genotypes. Therefore, we suggest that prenatal CPF exposure and VPA produce divergent effects on communication and anxiety.

Rapid appearance of negative emotion during oral fentanyl self-administration in male and female rats.

Opioid use disorder has become an epidemic in the United States, fuelled by the widespread availability of fentanyl, which produces rapid and intense euphoria followed by severe withdrawal and emotional distress. We developed a new preclinical model of fentanyl seeking in outbred male and female rats using volitional oral self-administration (SA) that can be readily applied in labs without intravascular access. Using a traditional two-lever operant procedure, rats learned to take oral fentanyl vigorously, escalated intake across sessions, and readily reinstated responding to conditioned cues after extinction. Oral SA also revealed individual and sex differences that are essential to studying substance use risk propensity. During a behavioural economics task, rats displayed inelastic demand curves and maintained stable intake across a wide range of fentanyl concentrations. Oral SA was also neatly patterned, with distinct 'loading' and 'maintenance' phases of responding within each session. Using our software DeepSqueak, we analysed ultrasonic vocalizations (USVs), which are innate expressions of current emotional state in rats. Rats produced 50 kHz USVs during loading then shifted quickly to 22 kHz calls despite ongoing maintenance of oral fentanyl taking, reflecting a transition to negative reinforcement. Using fibre photometry, we found that the lateral habenula differentially processed drug cues and drug consumption depending on affective state, with potentiated modulation by drug cues and consumption during the negative affective maintenance phase. Together, these results indicate a rapid progression from positive to negative reinforcement occurs even within an active drug taking session, revealing a within-session opponent process.

TrackUSF, a novel tool for automated ultrasonic vocalization analysis, reveals modified calls in a rat model of autism.

BACKGROUND: Various mammalian species emit ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interactions. USVs are usually analyzed by manual or semi-automated methodologies that categorize discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders the effective use of USVs as a readout for high-throughput analysis of behavioral changes in animals. RESULTS: Here we present a novel automated open-source tool that utilizes a different approach towards USV analysis, termed TrackUSF. To validate TrackUSF, we analyzed calls from different animal species, namely mice, rats, and bats, recorded in various settings and compared the results with a manual analysis by a trained observer. We found that TrackUSF detected the majority of USVs, with less than 1% of false-positive detections. We then employed TrackUSF to analyze social vocalizations in Shank3-deficient rats, a rat model of autism, and revealed that these vocalizations exhibit a spectrum of deviations from appetitive calls towards aversive calls. CONCLUSIONS: TrackUSF is a simple and easy-to-use system that may be used for a high-throughput comparison of ultrasonic vocalizations between groups of animals of any kind in any setting, with no prior assumptions.

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.

Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication.

Ventral Pallidum GABA Neurons Mediate Motivation Underlying Risky Choice.

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 role 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 WT littermates), using a reversible chemogenetic inhibition approach. Using 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 these neurons did not affect seeking of low-value food, free consumption of palatable food, or unconditioned affective responses to shock. Accordingly, when rats considered whether to pursue food despite potential for shock in a risky decision-making task, inhibiting VPGABA neurons caused them to more readily select a small but safe reward over a large but dangerous one, an effect not seen in the absence of shock threat. Together, results indicate that VPGABA neurons are critical for high-stakes adaptive responding that is necessary for survival, but which may also malfunction in psychiatric disorders.SIGNIFICANCE STATEMENT In a dynamic world, it is essential to implement appropriate behaviors under circumstances involving rewards, threats, or both. Here, we demonstrate a crucial role for VPGABA neurons in high-stakes motivated behavior of several types. We show that this VPGABA role in motivation impacts decision-making, as inhibiting these neurons yields a conservative, risk-averse strategy not seen when the task is performed without threat of shock. These new roles for VPGABA neurons in behavior may inform future strategies for treating addiction, and other disorders of maladaptive decision-making.