Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation

Matthews, Gillian A.; Nieh, Edward H.; Weele, Caitlin M. Vander; Halbert, Sarah A.; Pradhan, Roma V.; Yosafat, Ariella S.; Glober, Gordon; Izadmehr, Ehsan M.; Thomas, Rain E.; Lacy, Gabrielle D.; Wildes, Craig P.; Ungless, Mark A.; Tye, Kay M.

doi:10.1016/j.cell.2015.12.040

Cited by 305 publications

(278 citation statements)

References 73 publications

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“…Further testing employing these individual cellular resolution approaches or alternatively, fiber photometry directed toward explicit terminal fields (Chen et al, 2015), given the one-to-one ARC AgRP neural architecture (Betley et al, 2013), would begin to elucidate these questions. Importantly, projection-defined ARC AgRP neurons target a number of downstream areas that fail to elicit acute feeding behavior giving rise to the possibility that these efferents modulate surrogate behaviors such as mating and territorial aggression (Falkner and Lin, 2014; Matthews et al, 2016; Padilla et al, 2016; Yang and Shah, 2014). …”

Section: Discussionmentioning

confidence: 99%

Hunger-Driven Motivational State Competition

Burnett

Webber

et al. 2016

Neuron

226

223

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Summary Behavioral choice is ubiquitous in the animal kingdom and is central to goal-oriented behavior. Hypothalamic Agouti-related peptide (AgRP) neurons are critical regulators of appetite. Hungry animals, bombarded by multiple sensory stimuli, are known to modify their behavior during times of caloric need, rapidly adapting to a consistently changing environment. Utilizing ARCAgRP neurons as an entry point, we analyzed the hierarchical position of hunger related to rival drive states. Employing a battery of behavioral assays we found that hunger significantly increases its capacity to suppress competing motivational systems such as thirst, anxiety-related behavior, innate fear and social interactions often only when food is accessible. Furthermore, real-time monitoring of ARCAgRP activity revealed time-locked responses to conspecific investigation in addition to food presentation, further establishing that even at the level of ARCAgRP neurons choices are remarkably flexible computations integrating internal state, external factors and anticipated yield.

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Section: Discussionmentioning

confidence: 99%

Hunger-Driven Motivational State Competition

Burnett

Webber

et al. 2016

Neuron

226

223

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“…Sources of dopaminergic innervation of the Drd/Pet1 subtypes may include the rostral DR in addition to the SNc and midbrain VTA. While the midbrain VTA dopaminergic neurons have been shown to directly impact aggressive behaviors (Yu et al, 2014), the rostral DR dopaminergic neurons have recently been shown to influence the subjective experience of social isolation (Matthews et al, 2016). It remains to be definitively demonstrated, however, whether dopamine-mediated regulation of serotonergic neurons influences serotonin-mediated modulation of aggressive behaviors.…”

Section: Discussionmentioning

confidence: 99%

Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior

et al. 2016

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Summary Escalated aggression can have devastating societal consequences, yet underlying neurobiological mechanisms are poorly understood. Here we show significantly increased inter-male mouse aggression when neurotransmission is constitutively blocked from either of two subsets of serotonergic, Pet1+ neurons – one identified by dopamine receptor D1(Drd1a)::cre driven activity perinatally, the other by Drd2::cre from pre-adolescence onward. Blocking neurotransmission from other Pet1+ neuron subsets of similar size and/or overlapping anatomical domains had no effect on aggression compared to controls, suggesting subtype-specific serotonergic neuron influences on aggression. Using established and novel intersectional genetic tools, we further characterized these subtypes across multiple parameters, showing both overlapping and distinct features in axonal projection targets, gene expression, electrophysiological properties, and effects on non-aggressive behaviors. Notably, Drd2::cre-marked 5-HT neurons exhibited D2-dependent inhibitory responses to dopamine in slices, suggesting direct and specific interplay between inhibitory dopaminergic signaling and a serotonergic subpopulation. Thus, we identify specific serotonergic modules that shape aggression.

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“…Because serotonergic DR neurons influence postpartum physiology and behavior (Barofsky et al, 1983), their loss would be particularly impactful for the mothers. Additionally, the rostral DR is densely populated by dopaminergic neurons that encode the negative valence of social isolation and then drive the motivation to socially interact (Matthews et al, 2016). Elevated loss of these dopaminergic neurons during late lactation may facilitate weaning of the pups, which could otherwise produce aversive social isolation for the dams.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

Holschbach

Lonstein

2017

Psychoneuroendocrinology

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The adult brain shows remarkable neuroplasticity in response to hormones and the socioemotional modifications that they influence. In females with reproductive and maternal experience, this neuroplasticity includes the birth and death of new and existing cells in several forebrain regions involved in maternal caregiving and postpartum affective state. Such plasticity in midbrain sites critical for these processes has never been examined, though. Visualizing bromodeoxyuridine (BrdU) to label mitotic cells, l NeuroD for neuronal precursors, and TUNEL to identify dying cells, we found that the midbrain dorsal raphe nucleus (DR, the source of most ascending serotoninergic projections) exhibited significant neuroplasticity in response to motherhood. Specifically, BrdU analyses revealed that DR newborn cell survival (but not proliferation) was regulated by reproductive state, such that cells born early postpartum were less likely to survive compared to cells born during late pregnancy. Many of the surviving cells in the DR were NeuN immunoreactive, suggesting a neuronal phenotype. Similarly, late postpartum rats had fewer NeuroD-immunoreactive DR cells than early postpartum rats. Maternal experience contributed to the late postpartum reduction in DR newborn cell survival because removing the litter at parturition increased cell survival and reduced cell death. Unlike cytogenesis in the maternal hippocampus, which is reduced by circulating glucocorticoids, DR newborn cell survival was unaffected by postpartum adrenalectomy. These effects of reproductive state and motherhood on DR plasticity were associated with concurrent changes in DR levels of serotonin's precursor, 5-HTP, and its metabolite, 5-HIAA. Our results demonstrate for the first time that cytogenesis occurs in the midbrain DR of any adult mammal, that DR plasticity is influenced by female reproductive state and maternal experience, and that this plasticity is accompanied by changes in DR serotonergic function. Because serotonin is critical for postpartum caregiving behaviors and maternal affective state, neuroplastic changes in the DR may contribute to the neurochemical changes necessary for successful motherhood.

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Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation

Cited by 305 publications

References 73 publications

Hunger-Driven Motivational State Competition

Hunger-Driven Motivational State Competition

Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

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