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A neural substrate for negative affect dictates female parental behaviour

ABSTRACT: Parental behaviours are essential to secure survival and wellbeing of newborns. Concomitantly, parenting also limits negative affective states in adults, which emerge when the coping with neonatal distress becomes a challenge. Whether neural circuits that process negative affect orchestrate components of parental behaviours remains, however, unknown. Here, we identify functional and transcriptional signatures of parental behaviours in neurons of the negative emotion center lateral habenula receiving bed nucleus of the stria terminalis innervation (BNSTLHb). Calcium imaging and optogenetic manipulations reveal that LHb neurons of virgin female mice increase their activity in response to pup distress vocalization and are necessary for pup calls-driven aversive behaviours. Accordingly, LHb activity rises during the retrieval of a pup to a nest, a behaviour worsened by optogenetic LHb inactivation. Intersectional cell identification and transcriptional profiling associates the BNSTLHb neuronal population to parental behaviours and outlines gene expression in female virgins that is similar to mothers but divergent from non-parental virgin male mice. Accordingly, optogenetic activation and inactivation of the BNST-LHb pathway maximizes and suppresses, respectively, the parental behaviour. Finally, tracking and manipulating single BNSTLHb cell activity demonstrates specificity of this neuronal subset for encoding negative affect and pup retrieval, but not sociability amongst conspecifics. Thus, BNSTLHb cells are operational for female parenting, demonstrating that a negative affect neural circuit processes newborn distress signals and limits them through female parenting.

ORGANISM(S): Mus musculus

PROVIDER: GSE222064 | GEO | 2023/01/04

REPOSITORIES: GEO

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Project description:Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.

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A neural substrate for negative affect dictates female parental behaviour

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