Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

Abstract

All animals can perform certain survival behaviors without prior experience, suggesting a “hard wiring” of underlying neural circuits. Experience, however, can alter the expression of innate behaviors. Where in the brain and how such plasticity occurs remains largely unknown. Previous studies have established the phenomenon of “aggression training,” in which the repeated experience of winning successive aggressive encounters across multiple days leads to increased aggressiveness. Here we show that this procedure also leads to long-term potentiation (LTP) at an excitatory synapse, derived from the Anterior Hippocampus/Posterior Medial amygdala (AHiPM), onto estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate further that the optogenetic induction of such LTP in vivo facilitates, while optogenetic long-term depression (LTD) diminishes, the behavioral effect of aggression training, implying a causal role for potentiation at AHiPM➔VMHvlEsr1 synapses in mediating the effect of this training. Interestingly, ∼25% of inbred C57BL/6 mice fail to respond to aggression training. We show that these individual differences are correlated both with lower levels of testosterone, relative to mice that respond to such training, and with a failure to exhibit LTP in vivo after aggression training. Administration of exogenous testosterone to such non-aggressive mice restores both behavioral and physiological plasticity in vivo. Together, these findings reveal that LTP at a hypothalamic circuit node mediates a form of experience-dependent plasticity in an innate social behavior, and a potential hormone-dependent basis for individual differences in such plasticity among genetically identical mice.Significance StatementModification of instinctive behaviors occurs through experience, yet the mechanisms through which this happens have remained largely unknown. Recent studies have shown that potentiation of aggression, an innate behavior, can occur through repeated winning of aggressive encounters. Here we show that synaptic plasticity at a specific excitatory input to a hypothalamic cell population is correlated with, and required for, the expression of increasingly higher levels of aggressive behavior following successful aggressive experience. We additionally show that the amplitude and persistence of long-term potentiation at this synapse are influenced by serum testosterone, administration of which can normalize individual differences among genetically identical inbred mice, in the expression of intermale aggression.

Neural circuits of social behaviors: Innate yet flexible

“…This remains incompletely understood, but the answer is likely to be yes, at least partially. Stagkourakis et al (2020b) found that the testosterone level in non-aggressive males was low, and VMHvl cells in those animals failed to show LTP. When non-aggressive males were supplemented with testosterone, LTP was induced reliably, suggesting a permissive role of testosterone in synaptic potentiation at the VMHvl.…”

“…The synaptic potentiation between the amygdala and VMHvl could also be an essential mechanism for the winner effect. In a recent study, Stagkourakis et al (2020b) reported a significant increase in spontaneous EPSCs (sEPSCs) and the spine density of VMHvl cells in experienced winners in comparison with naive animals. The authors then focused on the projection from the PA-a major source of excitatory input to the VMHvl.…”

Mechanisms, development, and comparative perspectives on experience‐dependent plasticity in social behavior

“…Given the importance of birds and lizards to reveal ancestral phenotypes in vertebrates, we advocate for more studies in birds and lizards as well as other nonmammalian vertebrates. Indeed, as state‐of‐the‐art genetic techniques become more accessible to nonmammalian species, it will be important to assess the degree to which molecular mechanisms underlying experience‐dependent changes in mammals contribute to experience‐dependent plasticity in nonmammalian species (e.g., De Lorme et al, 2019; Inagaki et al, 2014; Pitchers et al, 2013; Stagkourakis et al, 2020).…”

Sensory-thresholded switch of neural firing states in a computational model of the ventromedial hypothalamus

“…Previous work showed that amygdala inputs to VMH convey predator and social threat information, [29,30] including pheromone/kairomone-based information about threat identity [11,[31][32][33] and polymodal information about threat intensity. [34][35][36][37][38] Because Assessment+, but not Flight+ neuron firing in vivo correlated linearly with inverse distance to threatand thus to the intensity of threatrelated sensory input [16] we explored both the simple condition under which Assessment, but not Flight cells received sensory input from Amygdala, and also conditions under which Assessment and Flight cells received varying relative Amygdala inputs (Flight = 0 to 100% Assessment input; see Methods). Throughout our study sensory input aimed at representing approach-to-flight behavior was modeled by repeated trains of brief, linearly increasing, and noisy excitatory input to Amygdala cells (Fig S2).…”

“…or postsynaptic origin and is a short-lasting non-linear neurotransmission mechanism described across many neuronal connections [39] including amygdala inputs to VMH. [37] We added short-term, presynaptic, facilitating plasticity to all core neuron outputs, including both core-core and core-shell synapses, in a model with varying Amygdala input density and symmetric feedback inhibition strength…”