1. Neuropeptidergic modulation of “internal states”
Neuropeptides are small molecules secreted from neurons. These molecules play important roles in modulating activities of the nervous system and are often associated with mental and psychiatric disorders. An important unanswered question is where and how in the brain these molecules work to influence an internal state linked to a specific behavioral outcome. One type of neuropeptide is often expressed in multiple locations in the brain, raising the possibility that one neuropeptide can have a different role at each of these locations. We have recently found that a neuropeptide called tachykinin modulates an internal state controlling aggressive behavior of Drosophila through a specific population of neurons. Interestingly, tachykinin is known to regulate aggression in animal models, such as mice, rats and cats.
We are investigating how tachykinin influences aggression-controlling downstream neural circuits, by comparing tachykinin’s functions in other parts of the brain. Tachykinins can be co-expressed with both excitatory and inhibitory neurotransmitters, which implies that the influence of tachykinin on neurons is context-dependent. We are currently characterizing intracellular genetic components that support transmission of tachykinin signaling. These findings will help us better understand how tachykinins influence aggressive arousal not only in the fly but in mammalian models, and may reveal potential molecular targets for medicines to better alleviate certain types of behavioral symptoms associated with mental and psychiatric disorders.
2. Synergy of neuromodulators on behaviors
Any given internal state is known to be modulated by multiple neuropeptides and monoamine neuromodulators. For example, tachykinin, neuropeptide Y, and serotonin are all involved in regulation of anxiety. How do so many modulators influence the same internal state? Do they converge on a single neural site controlling a given internal state, or do they act sequentially? We know relatively little about the way multiple neuromodulators interact to control a common internal state and corresponding behavior output. Interestingly, all three molecules mentioned above are known to influence Drosophila aggression. We are currently characterizing the nature of interactions among these three neuromodulators, both at genetic and circuitry levels. We hope to extract a general principle of neuromodulator cooperation on behavior-specific internal states.
3. Genetic and circuit basis of sexual dimorphisms in behavioral “internal states”
Gender differences in response to medicines, surgeriesnd other treatments have recently gained significant attention. In many animals, neural circuits and gene expression in the brain show considerable sexual dimorphism. An important question is how this dimorphism affects the internal states and corresponding behavioral outputs of an organism. Sexual dimorphisms in neural circuits and behavior have been well characterized in Drosophila. Namely, the tachykinin-expressing, aggression-controlling neurons show a male-specific dendritic arborization pattern, and tachykininergic signaling components are reported to be under the control of sex-determining genes. We are working to identify the genetic mechanisms with which the male aggression-controlling neurons attain characteristic morphology and gene expression patterns through comparison among different neuronal populations and homologous neurons in the female brain.
4. Neural substrates of “behavioral final common path”
An animal can perform only one behavior at any given moment. In fact, an animal usually “commits” to one behavior for a certain duration to ensure that purpose of the behavior is achieved. An internal state for the given behavior is likely sustained above threshold during this period of time. A failure to maintain the internal state can underlie unpredictable and unstable mood swings, and pathological fluctuation of the internal state, as evidenced in schizophrenia. We are conducting research on the genetic and neural mechanisms that support maintenance of behavior-specific internal states. We are trying to characterize the neural connections among known “behavior centers” in the Drosophila brain. We also plan to map motor output circuits for stereotypical behaviors, such as aggression and feeding, in order to illuminate how a common set of motor output circuits can be configured to perform a given behavior in an uninterrupted manner. These approaches may lead to the identification of neural substrates that represent “behavioral final common paths”, theoretically postulated more than 40 years ago.