Harvard University - Department of Molecular & Cellular Biology

SEXUALLY DIMORPHIC MAMMALIAN BRAIN FUNCTION AT THE SINGLE NEURON LEVEL [DULAC LAB]

by Joe Bergan

June 3rd, 2014

Catherine Dulac and Joe Bergan

An animal's survival depends critically on its ability to identify friends and foes in its environment and respond to each with suitable behaviors. For mice, chemical cues found in sweat, tears, urine, or saliva, provide an indispensible means to communicate with other members of their own species and to warn of potential dangers such as when a predator is nearby. These cues are detected by multiple 'olfactory' senses working in parallel, with the vomeronasal sensory system being particularly important for controlling innate behaviors and neuroendocrine functions. Although the anatomical details of the vomeronasal pathway have been broadly known for years, the manner in which sensory information is translated into appropriate actions by these brain circuits remains unknown. A recent study from the laboratory of Catherine Dulac begins to address these important issues.

Individual neurons distributed across the sensory epithelium of the vomeronasal organ respond to chemical cues. For example, one neuron might respond to a chemical emitted by male mice while another neuron may respond to a chemical emitted by predatory snakes. This information is then broadcast to the brain, specifically the accessory olfactory bulb, where the process of extracting behaviorally relevant information continues. In contrast to the apparent selectivity of the initial sensory neurons, neurons of the accessory olfactory bulb appear to combine multiple channels of information--perhaps comparing and contrasting distinct lines of sensory evidence to determine what animals are present in the environment.

Using in vivo electrophysiology in conjuncture with anatomical, pharmacological, and genetic techniques (Figure 1), Bergan et al. reveal that, neurons in the third stage of sensory processing, the medial amygdala, respond more selectively for distinct sensory cues-suggesting that the activity of a given medial amygdala neuron is devoted to a narrower array of sensory stimuli and behavioral outputs. Moreover, neurons with responses to similar sensory stimuli were consistently found in near each other and in stereotyped sub-regions of the medial amygdala. Therefore, the medial amygdala has a topographic organization of function such that specific regions are devoted towards distinct sensory and behavioral features.

Experimental system for recording MeA sensory responses. Top) Vomeronasal and olfactory structures are shown in yellow and blue, respectively. Multichannel electrophysiological probes are positioned in the MeA to continuously record neural responses to sensory stimulation. Middle) Timecourse of VNO stimulation trials. Bottom)  Electrophysiological signals recorded from a single MeA electrode during four successive trials reveal a well-isolated unit responding only to female stimuli.
 


Most striking, however, Bergan, Ben-Shaul, and Dulac found that the pattern of medial amygdala sensory responses was remarkably different in male versus female mice. While neurons in the accessory olfactory bulb respond similarly in male and female mice, medial amygdala neurons in male mice respond most strongly to female cues while those in female mice respond most strongly to male cues. This is the first direct demonstration of differences between the sensory processing in the brains of male and female mammals (Figure 2).

Sexual dimorphism of adult MeA responses.  Left) Responses of MeA neurons to vomeronasal stimuli in adult male (blue) versus female (red) mice. Each point represents the response profile of an individual unit, with at least one significant response, to male, predator, and/or female stimuli. Points located near a vertex represent units that respond most strongly for the stimulus indicated at that vertex whereas points at the center represent units that respond similarly to all stimuli. Right) A histogram showing the sex-specificity for all MeA units recorded from adult male (blue) and female (red) animals. Horizontal lines (above) indicate the mean and 95% confidence interval (bootstrap CI) of the mean for each distribution.
 

The authors next sought to determine when the difference in sensory responses first appears in the medial amygdala. By recording the sensory responses of neurons in animals before puberty, and comparing these responses to those observed in adult animals, the authors were able to show that the activity of medial amygdala neurons mirrors the development of sexually dimorphic behaviors. That is, in young animals the sensory responses of medial amygdala neurons are indistinguishable in male and female animals, but these same neurons begin to respond quite differently after puberty when differences in behavior also emerge. Like many sexually dimorphic behaviors, the
development of sexually dimorphic responses in the medial amygdala requires sex steroids for its expression.

These findings identify the medial amygdala as a central player in which critical information relevant to species- and sex-specific behaviors are extracted from complex natural stimuli. As well as increasing our understanding of the mechanisms by which chemical cues drive behaviors in mice, this work provides new insights into the neural mechanisms the mediate individual differences in behavior. Remarkably, the differences in MeA activity observed in each group of animals tested correlate tightly with the patterns of social behaviors from each of these groups. This suggests that the patterns of sensory responses in the medial amygdala likely underlie fundamental changes in social behavior exhibited by different animals and throughout development.

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