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1. Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

   https://doi.org/10.1073/pnas.2011890117  

   Duque-Wilckens, Natalia; Torres, Lisette Y.; Yokoyama, Sae; Minie, Vanessa A.; Tran, Amy M.; Petkova, Stela P.; Hao, Rebecca; Ramos-Maciel, Stephanie; Rios, Roberto A.; Jackson, Kenneth; et al (October 2020, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors. 

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2. A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression

   https://doi.org/10.7554/eLife.75470  

   Kim, Jessica H; Kromm, Grace H; Barnhill, Olivia K; Sperber, Jacob; Heuer, Lauren B; Loomis, Sierra; Newman, Matthew C; Han, Kenneth; Gulamali, Faris F; Legan, Theresa B; et al (May 2022, eLife)

   Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here, we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTN Tac1 neurons) and those that express corticotropin-releasing hormone (PSTN CRH neurons), and use a panel of genetically encoded tools in mice to show that PSTN Tac1 neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTN Tac1 , but not PSTN CRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTN Tac1 neurons, but not PSTN CRH neurons, reduces food intake in hungry mice. PSTN Tac1 and PSTN CRH neurons project to distinct downstream brain regions, and stimulation of PSTN Tac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTN Tac1 neurons in the hormonal and central regulation of appetite. 

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3. VTA Excitatory Neurons Control Reward-driven Behavior by Modulating Infralimbic Cortical Firing

   https://doi.org/10.1016/j.neuroscience.2024.03.012  

   Adeyelu, Tolulope; Vaughn, Tashonda; Ogundele, Olalekan M (June 2024, Neuroscience)

   Abstract—The functional dichotomy of anatomical regions of the medial prefrontal cortex (mPFC) has been tested with greater certainty in punishment-driven tasks, and less so in reward-oriented paradigms. In the infralimbic cortex (IL), known for behavioral suppression (STOP), tasks linked with reward or punishment are encoded through firing rate decrease or increase, respectively. Although the ventral tegmental area (VTA) is the brain region governing reward/aversion learning, the link between its excitatory neuron population and IL encoding of reward-linked behavioral expression is unclear. Here, we present evidence that IL ensembles use a population-based mechanism involving broad inhibition of principal cells at intervals when reward is presented or expected. The IL encoding mechanism was consistent across multiple sessions with randomized rewarded target sites. Most IL neurons exhibit FR (Firing Rate) suppression during reward acquisition intervals (T1), and subsequent exploration of previously rewarded targets when the reward is omitted (T2). Furthermore, FR suppression in putative IL ensembles persisted for intervals that followed reward-linked target events. Pairing VTA glutamate inhibition with reward acquisition events reduced the weight of reward-target association expressed as a lower affinity for previously rewarded targets. For these intervals, fewer IL neurons per mouse trial showed FR decrease and were accompanied by an increase in the percentage of units with no change in FR. Together, we conclude that VTA glutamate neurons are likely involved in establishing IL inhibition states that encode reward acquisition, and subsequent reward-target association. 

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4. Hedonic eating, obesity, and addiction result from increased neuropeptide Y in the nucleus accumbens during human brain evolution

   https://doi.org/10.1073/pnas.2311118120  

   Raghanti, Mary Ann; Miller, Elaine N.; Jones, Danielle N.; Smith, Heather N.; Munger, Emily L.; Edler, Melissa K.; Phillips, Kimberley A.; Hopkins, William D.; Hof, Patrick R.; Sherwood, Chet C.; et al (September 2023, Proceedings of the National Academy of Sciences)

   The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations. 

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5. Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters

   https://doi.org/10.3390/ijms24021379  

   Borland, Johnathan M.; Dempsey, Desarae A.; Peyla, Anna C.; Hall, Megan A.; Kohut-Jackson, Abigail L.; Mermelstein, Paul G.; Meisel, Robert L. (January 2023, International Journal of Molecular Sciences)

   Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions. 

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