Sensory physiology and brain circuits involved in chemosensory communication, including pheromones, studied by electrophysiological, anatomical and behavioral methods.
We study female to male and male to male signaling in golden hamsters and mice as a model to analyze sensory mechanisms; in particular, those leading to sensory control of behavior. Expression of Immediate-Early Gene products such as Fos- and FRA-proteins (from the c-fos gene or related genes) are used as markers to indicate which neurons in the brain change activity under different conditions, including:
- Chemosensory Stimulation
- Sexual Experience
- Hormone/ Neuromodulator Treatment (GnRH, Oxytocin, Dopamine, Androgen)
Direct-recording of neuronal electrical activity can also be used in some circumstances.
Our primary interest is in understanding the principles of brain-circuit operation and not the development of therapies. However, the unlearned recognition of chemo-sensory social signals that we study involves brain areas and circuits that have also been implicated in failures to recognize visual social signals, such as facial expressions, as in autism.
- We have mapped a functional pathway from Vomeronasal-Organ (VNO) and Olfactory sensory-neurons in the nose - through successive brain regions - to a region known to be critical for male mating behavior.
- We study the effect of chemosensory input to this pathway. (For more information on VNO, see: Vomeronasal Organ Website) Neurons along this pathway are active in males stimulated only by chemosensory stimuli - as well as in males that are actually mating.
- The chemosensory stimuli used here are natural, pheromone-containing, secretions from females. The initial, chemosensory parts of this pathway are also activated by natural chemosensory stimuli from males.
- Some part of this pathway must analyze the incoming neural signals in order to distinguish female and male stimuli from the same species, and to distinguish those socially-relevant stimuli from non-socially relevant stimuli that serve similar purposes -but in another species.
Sorting Socially Relevant from Non-relevant Stimuli
- The neurons in the first two brain regions receiving chemosensory input: the accessory olfactory bulb (AOB) and the anterior medial amygdala (MeA) respond to all stimuli, female, male, socially relevant or not; and from various species.
- Neurons in the posterior medial amygdala (MeP) only respond strongly to socially relevant stimuli (e.g. for hamsters, that means stimuli from female or male hamsters, NOT stimuli from mice: For mice, that means stimuli from female or male mice, not hamsters). This neural response reflects (or maybe causes?) normal behavioral responses.
- The amygdala is known to be concerned with social and sexual behavior in many species. Can circuits in MeA "filter out" non- relevant input - and not pass it on to MeP - or inhibit activity there when input is not relevant?
- In mice, the FRA activity-marker is also turned-on in ventral posterior medial amygdala by a biologically relevant stimulus from different species. Cat odor activates FRA in groups of cells overlapping with those activated by male conspecific stimuli. Are there common elements to defensive behavior against other males and against predators?
Effect of Experience, GnRH, Oxytocin, Dopamine on Chemosensory Transmission
- Removal of vomeronasal organs seriously impairs male mating behavior in sexually inexperienced male hamsters, but surgery after sexual experience has no effect. I.E. Experience changes the circuit -- allowing olfactory input to substitute for VNO input. What are these changes at the circuit and molecular level?
- GnRH hormone infused in the brain restores mating behavior lost through VNO removal. GnRH is a neurohormone that acts on the pituitary gland but is also released inside the brain. GnRH changes the circuit --allowing olfactory input to substitute for VNO input. What are these changes?
- Chemosensory activation of c-fos expression in medial amygdala changes with experience and with GnRH , but in different directions.
- Investigation of the changes in c-fos and electrical responses in the circuit with selective stimulation of VNO and olfactory systems reveals changes in transmission of chemosensory information as a result of these two manipulations.
- The amygdala is known to be involved with learning of certain types. The neuronal “circuit’ for chemosensory-related learning similar to that (e.g.) for fear conditioning?
- Mice that lack Oxytocin expression (OT-KO) fail to recognize other mice they have encountered. The c-Fos expression in these mice suggests there is a failure of chemosensory mechanisms. Injections of Oxytocin-Antagonist (OT-A, which blocks OT action) eliminates medial amygdala response to chemical signals, including cat odor – and mice no longer avoid cat odor. Oxytocin appears to be necessary for both the normal amygdala response and for normal behavioral recognition of the meaning of stimuli.
- Dopamine modulates circuits in the amygdala to switch from a more cognitive (cortically driven) response to stimuli, to a more stereotyped (emotional?) response. The same dopamine-target neurons can also alter chemosensory circuits. Current experiments evaluate whether DA modulates unlearned as well as learned responses?
Amygdala Circuits that Discriminate Different Stimuli
- Posterior medial amygdala (MeP) is selectively inactivated by stimuli not relevant for the responding animal. At the same time, a small group of inhibitory GABA-containing cells (the main intercalated nucleus; mICN) is activated, suggesting these cells may inhibit MeP.
- This prediction is being investigated in experiments with brain tissue maintained in vitro by perfusion with oxygenated solution. In preliminary results, electrical responses from single neurons in MeP show hyper-polarization and inhibition when mICN is stimulated.
- This circuit organization, with a small GABA-ergic cell group modulating response of a principal amygdala region is similar to those of other amygdala regions that evaluate different kinds of stimuli (e.g. auditory or visual stimuli used in fear-conditioning experiments), suggesting stimulus recognition for different kinds of sensory stimuli might be accomplished by a common circuit-mechanism but in different amygdala regions.