Research in Mark Baxter’s laboratory, the Glickenhaus Laboratory of Neuropsychology, focuses on the neural systems underlying memory and other higher cognitive functions, and understanding how disturbances in these systems impair cognitive function in brain disorders. Our general approach is to study the effects on behavior of specific manipulations of neural circuits in animal models, to gain insight into how similar disruptions in human disease may be responsible for cognitive impairment.
We have a long-standing interest in the role of the neurotransmitter acetylcholine in cognitive function. Acetylcholine has been closely identified with memory and other cognitive functions in part because levels of acetylcholine are reduced in the neocortex of patients with Alzheimer’s disease. Three of the four FDA-approved drugs for Alzheimer’s disease function by inhibiting the breakdown of acetylcholine in the central nervous system. We have recently identified a possible new role of acetylcholine in cognitive impairments in neurodegenerative diseases, through a series of studies in monkeys using a selective neurotoxin for neurons in the brain that use acetylcholine as their neurotransmitter. We found that the memory-impairing effects of damage to brain structures important for episodic memory (memory for events) were exacerbated by prior loss of acetylcholine in the cortex of monkeys. This effect depended on the order in which the brain manipulations occurred: removing acetylcholine after structural damage had already occurred had no effect on the severity of memory impairment. These findings suggest that acetylcholine may ordinarily enable some recovery of episodic memory function after damage to neural circuitry involved in episodic memory function. The loss of acetylcholine in conditions like Alzheimer’s disease may disable this recovery. This provides a possible mechanism by which drugs that increase brain acetylcholine levels are sometimes able to slow the rate of functional decline in Alzheimer’s disease.
We are currently working on developing new tools for reversibly inhibiting and stimulating specific populations of nerve cells in the brains of awake, behaving monkeys as they perform cognitive tasks. This will help us answer questions about the neurobiology of memory retrieval, by reversibly silencing specific groups of neurons and testing memory while those neurons are active or inactive in the same animal. The ability to increase the activity of specific groups of neurons may provide a means to boost impaired memory retrieval when memories have degraded as a consequence of the passage of time (forgetting) or as a consequence of brain disease.