Five for Fighting: experience and testosterone shape aggressive behavior
Aggression-training results in VMHvlEsr1neurons to have greater number and size of dendritic spines (blue).
In Chapter 10 of the Principles of Neurobiology, we learned about sex and sexual dimorphism of neural circuits in invertebrate (PoN Sections 10.1–10.8) and vertebrate animal models (Sections 10.9–10.16). In mammals, the sex hormones testosterone and estradiol shape sexually dimorphic neural circuits during behavior and maintain sex-typical behavior in adulthood (Sections 10.10–10.11). Discrete brain regions in rodents have been identified that contain sexually dimorphic circuits that control sexually dimorphic behavior. The ventromedial hypothalamus (VMH), for example, contains sex hormone-expressing neurons that can control female and male mating behavior as well as male aggression behavior (Section 10.15).
How are innate behaviors shaped by experience in neural circuits? While we generally consider sexually dimorphic behaviors as a repertoire of innate behaviors that do not require learning, innate behaviors have been shown to be modified by experience as well (e.g., PoN Figure 10-32). In a recent study by Stagkourakis and colleagues, the authors explore the experience-dependent component of male territorial aggression, identifying synaptic plasticity via long-term potentiation (LTP) in Esr1-expressing neurons of the ventrolateral part of the VMH (VMHvlEsr1 neurons). LTP has been extensively studied in areas of cognitive processing such as the hippocampus (Sections 11.4–11.18), but its role in the hypothalamus has been only sparsely studied in the past.
Stagkourakis et al., show that following a 5-day regime of aggression training in male mice, 75% maintain a propensity for territorial aggression up to 90 days after onset of training, while 25% do not respond to aggression training (Fig 1A–F). The authors designated these mice aggressive (AGG) and non-aggressive (NON), respectively. ex vivo slice physiology experiments showed that AGG VMHvlEsr1 neurons had greater Ca2+ activity (Fig 1G–J) and higher frequency and amplitude of spontaneous EPSCs compared to NON VMHvlEsr1 neurons (Fig 2A–C).
Hypothesizing that LTP-like mechanisms may underlie the experience-dependent behavioral and neuronal changes of AGG mice, the authors first identified an excitatory input projection to VMHvlEsr1 neurons from the amygdalo-hippocampal area (AHiPM, also known as posterior amygdala). Because the AHiPM-VMHvlEsr1 projection is excitatory and mostly monosynaptic, the authors were able perform in slice and in vivo potentiation experiments on VMHvlEsr1 neurons. Leveraging this projection with optogenetic techniques, the authors showed that AGG VMHvlEsr1 neurons showed evidence of undergoing LTP through aggression training (Fig 2I–M). In addition, AGG VMHvlEsr1 dendrites showed extensive evidence of structural plasticity (Fig 3). The authors then directly induced LTP and long-term depression (LTD) in slice and in vivo by optogenetics (Fig 4), and they showed that optogenetic LTP facilitates aggression learning while LTD abolishes aggression learning (Fig 5).
Finally, the authors investigate why the non-aggressive mice are resistant to aggression training. Reasoning that the activational role of sex hormones (PoN Section 10.10) may influence efficacy of aggression training, the authors quantified serum testosterone (T) levels and found that AGG mice have greater T through the course of training (Fig 6A–D). To causally test whether T levels affect aggression training efficacy, the authors showed that NON mice treated with exogenous T showed robust aggressive behavior (Fig 6G–J) and enhanced LTP induction in slice (Fig 6K–O) and in vivo (Fig 6Q–T).
In the work of Stagkourakis and colleagues, we gain a glimpse into how experience and hormones modify the neural circuits that regulate sexually dimorphic behavior. How does T implement gene expression changes that permit aggression training? Does T act on VMHvlEsr1 neurons in a cell-autonomous manner? Many questions remain, and the model circuit that Stagkourakis et al. establishes allows further exploration of how sex hormones, experience, and plasticity interactively modulate a discrete neuronal ensemble.
Reference
Stagkourakis, Stefanos, Giada Spigolon, Grace Liu, and David J. Anderson. "Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP." Proceedings of the National Academy of Sciences 117, no. 41 (2020): 25789-25799. Link