Probes for INS

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and coordinate social interactions. However, the neural circuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors, comprises molecularly diverse neurons with widespread projections. Here we identify a steroid-responsive subset of neurotensin (Nts)-expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially engaged reward circuit. Using in vivo two-photon imaging in female mice, we show that mPOANts neurons preferentially encode attractive male cues compared to nonsocial appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue-encoding properties of these cells. Furthermore, optogenetic stimulation of mPOANts-VTA circuitry promotes rewarding phenotypes, social approach and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically relevant stimuli and co-opt midbrain reward circuits to promote prosocial behaviors critical for species survival.

To deconstruct the architecture and function of brain circuits, it is necessary to generate maps of neuronal connectivity and activity on a whole-brain scale. New methods now enable large-scale mapping of the mouse brain at cellular and subcellular resolution. We developed a framework to automatically annotate, analyze, visualize and easily share whole-brain data at cellular resolution, based on a scale-invariant, interactive mouse brain atlas. This framework enables connectivity and mapping projects in individual laboratories and across imaging platforms, as well as multiplexed quantitative information on the molecular identity of single neurons. As a proof of concept, we generated a comparative connectivity map of five major neuron types in the corticostriatal circuit, as well as an activity-based map to identify hubs mediating the behavioral effects of cocaine. Thus, this computational framework provides the necessary tools to generate brain maps that integrate data from connectivity, neuron identity and function.

Classical mechanisms through which brain-derived molecules influence behavior include neuronal synaptic communication and neuroendocrine signaling. Here we provide evidence for an alternative neural communication mechanism that is relevant for food intake control involving cerebroventricular volume transmission of the neuropeptide melanin-concentrating hormone (MCH). Results reveal that the cerebral ventricles receive input from approximately one-third of MCH-producing neurons. Moreover, MCH cerebrospinal fluid (CSF) levels increase prior to nocturnal feeding and following chemogenetic activation of MCH-producing neurons. Utilizing a dual viral vector approach, additional results reveal that selective activation of putative CSF-projecting MCH neurons increases food intake. In contrast, food intake was reduced following immunosequestration of MCH endogenously present in CSF, indicating that neuropeptide transmission through the cerebral ventricles is a physiologically relevant signaling pathway for energy balance control. Collectively these results suggest that neural-CSF volume transmission signaling may be a common neurobiological mechanism for the control of fundamental behaviors.

The basal ganglia (BG) integrate inputs from diverse sensorimotor, limbic, and associative regions to guide action-selection and goal-directed behaviors. The entopeduncular nucleus (EP) is a major BG output nucleus and has been suggested to channel signals from distinct BG nuclei to target regions involved in diverse functions. Here we use single-cell transcriptional and molecular analyses to demonstrate that the EP contains at least three classes of projection neurons-glutamate/GABA co-releasing somatostatin neurons, glutamatergic parvalbumin neurons, and GABAergic parvalbumin neurons. These classes comprise functionally and anatomically distinct output pathways that differentially affect EP target regions, such as the lateral habenula (LHb) and thalamus. Furthermore, LHb- and thalamic-projecting EP neurons are differentially innervated by subclasses of striatal and pallidal neurons. Therefore, we identify previously unknown subdivisions within the EP and reveal the existence of cascading, molecularly distinct projections through striatum and globus pallidus to EP targets within epithalamus and thalamus.

Type I spiral ganglion neurons (SGNs) transmit sound information from cochlear hair cells to the CNS. Using transcriptome analysis of thousands of single neurons, we demonstrate that murine type I SGNs consist of subclasses that are defined by the expression of subsets of transcription factors, cell adhesion molecules, ion channels, and neurotransmitter receptors. Subtype specification is initiated prior to the onset of hearing during the time period when auditory circuits mature. Gene mutations linked to deafness that disrupt hair cell mechanotransduction or glutamatergic signaling perturb the firing behavior of SGNs prior to hearing onset and disrupt SGN subtype specification. We thus conclude that an intact hair cell mechanotransduction machinery is critical during the pre-hearing period to regulate the firing behavior of SGNs and their segregation into subtypes. Because deafness is frequently caused by defects in hair cells, our findings have significant ramifications for the etiology of hearing loss and its treatment.