College of Medicine
Department of Neuroscience, Psychology and Psychiatry
- The use of animal models to study the psychobiology of attentional dysfunctions, particularly as they contribute to the cognitive deficits seen in aging and neuropsychiatric disorders such as Alzheimer's dementia, schizophrenia and compulsive drug use
- Sparing and recovery of function after brain damage, particularly the influence of age (early developmental and aging) on plasticity following trauma or disease
Current Research: Dr. Bruno's laboratory focuses on issues in neuropsychopharmacology. Currently they are engaged in preclinical neuroscience research, studying the neurochemical mechanisms underlying attentional deficits in aging and various neuropsychiatric disorders.
The objectives of this research are to better understand the way the brain mediates early stages of information processing — such as the detection, selection and processing of stimuli — and to design and test more effective pharmacotherapies for the treatment of attentional dysfunctions.
There is considerable literature implicating cortical cholinergic transmission in attentional processing. Together with his collaborator, Dr. Martin Sarter, Dr. Bruno and his team have proposed that dysregulations of cortical cholinergic transmission result in different types of attentional impairments. Over time, these impairments may contribute to the development of certain cognitive deficits seen in several neuropsychiatric disorders.
One of the lab's research programs focuses on animal models of aging and Alzheimer's dementia. The cognitive deficits seen during aging and Alzheimer's dementia are highly correlated with declines in cortical cholinergic transmission. Thus, they are studying ways to enhance the release of cortical acetylcholine (ACh) in these animals.
To date, attempts to improve cognition by increasing cortical cholinergic transmission with cholinesterase inhibitors or direct muscarinic agonists have not led to a significant enhancement of cognition.
Dr. Bruno's lab is testing the hypothesis that the temporal synchrony between cortical ACh release and incoming sensory information is critical for early stages of information processing (e.g., attention). Thus, previous strategies for simply increasing cortical ACh release independent of the level of cortical activation would not be predicted to be therapeutic.
The lab's strategy has been to more physiologically enhance cortical cholinergic transmission by increasing the excitability of the basal forebrain cholinergic neurons. These neurons are inhibited by GABAergic afferents. They can reduce the degree of inhibition by negatively modulating GABAergic transmission using benzodiazepine receptor inverse agonists. Dr. Bruno's lab is also studying nicotinic receptor agonists as a means of potentiating the release of ACh in cortex. With these strategies, cortical ACh release is enhanced only under situations in which the cholinergic neurons are being naturally stimulated — thereby preserving the critical temporal synchrony between cortical cholinergic receptor activity and incoming sensory information.
A second research program in the laboratory involves the modeling of clinical conditions that reveal attentional deficits that are opposite, in a sense, to those seen in aging and Alzheimer's dementia. For example, in schizophrenia there is a dysfunctional overprocessing of stimuli. This hypervigilance to certain sensory stimuli makes it extremely difficult to disattend — a critical component of normal information processing — and can result in a pathological exhaustion of processing capacity.
Dr. Bruno's lab has also proposed that such a hyperattentional overprocessing of drug-related stimuli contributes to the drug craving and relapse seen in compulsive drug use. Their hypothesis is that the basal forebrain cholinergic system is pathologically overactive in these clinical conditions and contributes to the accompanying attentional dysfunctions. Thus, they are investigating strategies to dampen the excitability of cortical cholinergic transmission in animal models of schizophrenia and drug use. Researchers are studying the effects of dopamine receptor antagonists (typical and atypical antipsychotics), glutamate receptor antagonists and benzodiazepine receptor agonists on cortical ACh release in animals as they perform an operant task measuring sustained attention.
Students in Dr. Bruno's laboratory currently have the opportunity to learn and use the following techniques in their research:
Behavioral: Sophisticated operant techniques designed to measure sustained attention or conditioned reward
Neurochemical: Simultaneous measurement of neurotransmitter efflux (e.g., ACh, DA, GABA and Glutamate) from multiple brain regions in behaving animals. Measurements used include microdialysis, immunohistochemical measurement of transmitters, associated enzymes and immediate early genes (e.g., c-fos) as markers of neuronal activity Other techniques: Stereotaxic brain surgery, infusions of drugs and selective neurotoxins into discrete brain regions
Degree: Johns Hopkins University
Postdoctoral: University of Pittsburgh, Dr. Edward Stricker and Dr. Michael Zigmond; North Carolina Division of Mental Health (Dorothea Dix Hospital), Dr. Warren G. Hall