Neurobiology

Jonathan B. Cohen, Ph.D.

Identifying Binding Sites for Nicotinic Acetylcholine Receptor Allosteric Modulators

(Professor, Dept. Neurobiology, Harvard Medical School)

One of the first recognized deficits of Alzheimer’s Disease (AD) is the perturbation of the pathways in the brain using acetylcholine (ACh) as the neurotransmitter, and dysfunction of those neurons contributes to the cognitive decline characteristic of AD. Drugs that inhibit acetylcholinesterase, the enzyme that degrades ACh, are one of the few classes of drugs approved by the FDA for treatment of AD, as they are recognized to slow the decline of cognitive function. Nicotine, an agonist (activator) of all nicotinic acetylcholine receptors (nAChRs), is an effective cognitive enhancer, and the α4β2 and α7 nAChR subtypes have been identified as important targets for the development of novel therapeutic targets for Alzheimer’s Disease.

The goal of this project is to initiate experiments that will lead to the identification of the mechanism of action of drugs that act as α4β2 or α7 nAChR positive allosteric modulators, i.e. drugs that do not on their own activate the receptor but bind elsewhere on the receptor and act to potentiate the action of the ACh. Positive allosteric modulators represent an important, novel class of therapeutic agents as they will enhance the efficacy of endogenous neurotransmitter signaling while avoiding the prolonged, non-physiological pattern of receptor activation produced by agonists. We will develop photoreactive allosteric modulators that can be incorporated covalently into their binding sites in the nAChR, and we will use protein chemistry techniques to directly identify the receptor amino acids contributing to the drug binding sites.

It is our hypothesis that drugs may bind, depending upon structure, to sites either in the extracellular or transmembrane domains of the receptors, and we will identify the diversity of allosteric modulator binding sites by use of appropriate photoreactive analogs.

Lisa V. Goodrich, Ph.D.

A Cre-dependent RNAi screen for genes that regulate auditory circuit assembly

(Associate Professor, Dept. Neurobiology, Harvard Medical School)

Our long term goal is to understand how a naïve precursor differentiates into a specific subtype of neuron with specialized signaling properties and precise patterns of connectivity. Towards this end, we are dissecting the cellular and molecular events that occur during the development of a single, well-defined neuronal cell population that mediates an obvious behavior: the auditory neurons of the inner ear.

In the past, studies of the inner ear have been hampered by its small size and inaccessibility. We solved these problems by using genetically-encoded reporters to visualize auditory neurons along their entire trajectory and at any stage of development, down to the level of the synapse. This same approach makes it possible to easily detect wiring defects in the inner ear of mutant mice. Moreover, we are able to test hearing in mutant animals and demonstrate even subtle changes in auditory processing. Together, these genetic tools make it possible to engineer changes in auditory circuits and then determine the consequences for hearing.

To build on these results, the aim of our Lefler-funded research is to develop a novel method that we will use to mutate genes hypothesized to act specifically in auditory neurons, simultaneously visualize the morphologies of the mutant neurons, and detect changes in the perception of sound in mutant animals. As well as providing insights into the normal wiring of the auditory system, this method can be adapted in the future to identify genes that act in any other region of the nervous system to control fate, wiring, survival or function.

Sandeep Robert Datta, M.D., Ph.D.

Exploring the Mechanisms of Odor-Driven Neurogenesis

(Assistant Professor, Dept. Neurobiology, Harvard Medical School)

Sensory systems detect critical information in the environment, transmit this information to the brain, and process this information into an internal representation of the external world. These sensory maps are coupled to higher brain centers to generate behaviors. However, these circuits are not static; sensory information continuously remodels this wiring to allow animals to dynamically respond to their environment. These updates are implemented through activity-dependent changes in gene expression and message translation that ultimately alter the anatomic and electrical properties of neurons and neural circuits. Recent data also demonstrates that sensory cues trigger the generation and integration of new neurons into the adult nervous system, suggesting that adult neurogenesis may play an important role in the adaptibility of sensory circuits. Consistent with this possibility, adult neurogenesis is critical for certain learning-driven behavioral changes associated with specific sensory triggers such as odors. We propose experiments to characterize how odors drive adult neurogenesis, and how newly generated neurons impinge upon olfactory circuits. Understanding these processes will lead both to insights into the physiological function of neural stem cells and to strategies for repairing neural circuits damaged by disease.