Neuronal Processing underlying Reproductive Function
What does computation have to do with reproductive function?
After all, thinking is unnecessary and usually even disruptive for sex. Nevertheless, sexual motivation and behavior are both outcomes of non-trivial computations. To execute these computations, the brain must evaluate information about the potential partner, the environment, and the individual itself. Integration of sensory inputs with internal states is a general issue that the brain has to solve for various types of behaviors, not just reproduction. One reason for focusing on reproduction is that it involves relatively stereotyped neuronal circuitry – this facilitates their analysis. More importantly, these behaviors are simply fascinating to us, in animals, and even more so in humans. Our broad goal then, is to understand how the brain integrates sensory information with the individual’s internal physiological state to control reproductive physiology and behavior.
How are socially relevant chemical cues detected and processed to control reproductive function?
Sexual behavior and sexually related physiological changes are controlled by neurons in the hypothalamus, a brain region with numerous sub-divisions containing intermixed and interrelated neuronal populations. To a large extent, these hypothalamic populations are conserved among species, and thus studies in mammalian animal models are highly relevant to humans. Yet, there are major differences among species in the sensory modalities that modulate these hypothalamic populations. While in humans, vision, olfaction, audition, and touch all play important roles, in rodents (which account for most mammalian species), chemosensation is the dominant modality.
In mice, chemical cues are detected by multiple chemosensory systems. Our research primarily involves the vomeronasal system because it is strongly implicated it in controlling reproductive function. Indeed, vomeronasal sensory neurons are a major source of input to hypothalamic neurons. Yet, they do not target hypothalamic neurons directly. Rather, the immediate target of vomeronasal sensory neurons is the accessory olfactory bulb (AOB), which is thus the first brain region with access to vomeronasal chemosensory information. Accessory olfactory bulb neurons then send axons to more centrally located regions, primarily to the vomeronasal amygdala which contains neurons that directly reach the hypothalamus. This completes a pathway that starts with stimulus detection at the vomeronasal organ and ends with hypothalamic activation.
The brain regions that link vomeronasal sensory neurons to the hypothalamus are not merely passive relays. Instead, each has distinct roles in the process of combining sensory information with external states to control reproductive function. On a phenomenological level, we study the neuronal activity in each of these brain regions upon exposure to various sensory cues and under various internal states. Such experiments have already provided important insights on the distinct features of each of these brain regions. However, a mechanistic understanding of information processing involves understanding the functional links between neurons in different brain regions and between internal sensors of the physiological state and these neurons. We believe that both lines of research are required to provide a complete explanation of the neuronal control of reproductive function.
Experimental approaches: Electrophysiology, optogenetics, and behavior
We use multisite extracellular recordings to sample large populations of neurons, and intracellular recordings to monitor the events occurring within a neuron and also to analyze its structure and how it is related to its function. Our lab also employs optogenetic tools to record the activity of specific, genetically defined neuronal populations and to reveal how activation of specific neuronal populations (including those in the hypothalamus) modulate reproductive behavior and physiology. Finally, we are also testing how reproductive physiology and behavior are modulated by activation of specific neuronal populations.
In-vivo electrophysiology allows us to monitor neuronal activity at the resolution of individual neurons in the intact animal (mouse) at the ms resolution. This resolution is important, because experiments by us and others show that adjacent neurons can display very different responses to any given stimulus, and because the temporal dynaics of neuronal responses are highly relevant to information processing.
One of the challenges of studying the vomeronasal system is the nature of stimulus access. Vomeronasal sensory neurons are located within a dedicated organ, the vomeronasal organ (VNO), which is in fact a pump that sucks stimuli from the floor of the nasal cavity. Exposure of vomeronasal sensory neurons to chemical stimuli requires active pumping. The location of these sensory neurons within the VNO effectively implements a gating mechanism. That is, vomeronasal sensory neurons can only detect stimuli when the organ is activated, and the organ is activated mainly during states of arousal. Fascinating as it is, this unique mode of active stimulus delivery imposes a technical difficulty: when measuring responses in the brain, how can we know that stimuli indeed reached vomeronasal sensory neurons? Our solution to this problem involves an experimental preparation that allows us to activate the pumping action at will. Thus, we can anesthetize a mouse, expose the system to various sensory stimuli and measure the responses using electrodes.
This approach has shown that some neurons in the accessory olfactory bulb respond very selectively to stimuli from a given sex, a given genetic background, or even a specific individual. At the same time, mouse accessory olfactory bulb neurons can also selectively respond to stimuli that are not from mouse origin, for example, predator stimuli. One of the surprising features of some AOB neurons is that they can be activated by very distinct types of stimuli, for example mouse urine and predator urine. Another features is that AOB neurons in males and in females show similar response properties. Thus, our working model is that the main function of this early stage is to process external sensory features without evaluating their behavioral implications. We assume that judgments about attractiveness, or integration with other physiological aspects are done elsewhere – for example in the vomeronasal amygdala or in other regions that also receive inputs from the reward centers of the brain. Specific projects in the lab are focused on understanding how a given stimulus is represented by various brain regions and how these representations are modulated by an organism’s physiological state and prior experience.
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Education and Occupation
Senior Lecturer at the Hebrew University Faculty of Medicine.
Postdoctoral fellow (Harvard University, with Prof. Catherine Dulac)
Postdoctoral fellow (Duke University, Prof. Lawrence C. Katz and Prof Richard Mooney)
Postdoctoral fellow (Hebrew University, Prof Hagai Bergman and Prof. Hermona Soreq)
PhD in neuronal computation "Neuronal activity related to generation of complex movements". Summa cum Laude. (supervised by Prof Moshe Abeles)
B.Sc. Summa cum Laude Biology/Amirim, Hebrew University