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

 View ORCID Profile Stefanos Stagkourakis, 

 View ORCID Profile Giada Spigolon, 

 View ORCID Profile Grace Liu, and David J. AndersonPNAS first published September 24, 2020; https://doi.org/10.1073/pnas.2011782117

  1. Contributed by David J. Anderson, August 25, 2020 (sent for review June 9, 2020; reviewed by Robert C. Malenka and Richard Mooney)


Modification 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 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 in the expression of intermale aggression among genetically identical mice.


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 posteromedial part of the amygdalohippocampal area (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 after aggression training. Administration of exogenous testosterone to such nonaggressive mice restores both behavioral and physiological plasticity. 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.

Brains evolved to optimize the survival of animal species by generating appropriate behavioral responses to both stable and unpredictable features of the environment. Accordingly, two major brain strategies for behavioral control have been selected. In the first, “hard-wired” neural circuits generate rapid innate responses to sensory stimuli that have remained relatively constant and predictable over evolutionary timescales (12). In the second, neural circuits generate flexible responses to stimuli that can change over an individual’s life span, through learning and memory (34).

One common view is that these two strategies are implemented by distinct neuroanatomical structures and neurophysiological mechanisms. According to this view, in the mammalian brain, innate behaviors are mediated by evolutionarily ancient subcortical structures, such as the extended amygdala and hypothalamus, which link specific sensory inputs to evolutionarily “prepared” motor outputs through relatively stable synaptic connections (5). In contrast, learned behaviors are mediated by more recently evolved structures, such as the cortex and hippocampus, which compute flexible input–output mapping responses through synaptic plasticity mechanisms (6). This view has been supported by studies that have revealed distinct anatomical pathways through which olfactory cues evoke learned vs. innate behaviors in both the mouse (79) and in Drosophila (reviewed in ref. 10).

This view of distinct neural pathways for innate vs. learned behaviors, however, is challenged by the case of behaviors that, while apparently “instinctive,” can nevertheless be modified by experience. For example, studies in rodents have shown that defensive behaviors such as freezing can be elicited by both unconditional and conditional stimuli, the latter via Pavlovian associative learning (reviewed in ref. 11). In this case, the prevailing view argues for parallel pathways: Conditioned defensive behavior is mediated by circuitry involving the hippocampus, the thalamus, and the basolateral/central amygdala whereas innate defensive responses to predators are mediated by the medial amygdala (MeA)/bed nucleus of the stria terminalis (BNST) and hypothalamic structures (reviewed in ref. 12). Although the basolateral amygdala contains representations of unconditioned aversive and appetitive stimuli, these representations are used as the cellular substrate for pairing with conditioned stimuli (1314). Despite this segregation of learned and innate defensive pathways, it remains possible that experience-dependent influences on other innate behaviors may involve plasticity at synapses that directly mediate instinctive behaviors.

We have investigated this issue using intermale offensive aggression in mice. While aggression has been considered by ethologists as a prototypical innate behavior (1516), animals can be trained to be more aggressive by repeated fighting experience (1719). The neural substrates and physiological mechanisms underlying this form of experience-dependent plasticity remain unknown. Interestingly, inbred strains of laboratory mice exhibit individual differences in this form of plasticity, with up to 25% of animals failing to respond to aggression training (19). The biological basis of this heterogeneity is not understood. Here, we provide data supporting a plausible explanation for both experience-dependent changes and individual differences in male aggressiveness, one that links physiological plasticity at hypothalamic synapses to aggressive behavior and sex hormone levels.

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About S. R. Zelenz 119 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.