Robert Mair - US grants

The pathologic basis of amnesia is obscure. Diseases that produce amnesia in humans are often accompanied by a number of pathologic alterations, both structural and neurochemical, that have been linked hypothetically with learning and memory impairments. We have focused our research on Korsakoff's syndrome, a common cause of diencephalic amnesia that is believed to result from a subacute bout of thiamine deficiency. In an initial series of experiments, we developed an animal model of this disease, the post thiamine deficiency (or PTD) rat. Our investigations of the PTD model have demonstrated: i. behavioral impairments consistent with global anterograde amnesia; ii. changes in indices of neurotransmitter activity measured in local brain regions; iii. thalamic lesions that resemble those of Korsakoff's syndrome in histologic appearance and in topographic distribution in medial thalamus; iv. a consistent coincidence between the occurrence of medial thalamic lesions and behavioral deficits; and v. a general sparing of other extrathalamic structures that have been implicated as being important for learning and memory. The immediate goal of this proposal is to determine whether thalamic lesions can account for the learning and memory impairments of the PTD rat. This goal will accomplished in two ways. First, we will determine whether comparable behavioral impairments can be produced by experimental lesions in thalamic sites commonly associated with pathology in the PTD model. Second, we will determine if rats subjected to PTD treatment, but protected from thalamic lesions by MK-801 treatment, also have a spared ability to learn tasks requiring representational memory. From a broader perspective, this line of research will build on the results of the PTD studies to address several critical issues concerning the role of thalamic mechanisms in learning and memory, namely: i. identifying critical sites at which thalamic lesions impair learning and memory; ii. determining the nature of learning and memory impairments produced by thalamic lesions; and iii. considering possible interactions between thalamic lesions and neurotransmitter systems in the production of diencephalic amnesia.

The mediodorsal (MD) and adjacent reuniens (Re) and intralaminar (IL) nuclei are prominent components of central thalamus that are organized to provide rapid and precise modulatory control of distributed neural networks involving medial prefrontal cortex (mPFC) that support adaptive goal-directed behavior. The essential role of these nuclei in cognition and awareness has been established by clinical and preclinical studies of neurological and psychiatric disorders that affect them. There is surprisingly little known about the activity of neurons in these nuclei and how they influence the networks they innervate during goal- directed behavior. We propose to address this gap in our knowledge by studying neuronal activity in rats performing dynamic delayed nonmatching to position (dDNMTP): a task that incorporates critical features of goal-directed behavior affected by mPFC, hippocampal, and central thalamic lesions. Preliminary studies were conducted to compare coding properties of neurons in MD and mPFC and to examine the effects of inactivating central thalamus on mPFC activity during dDNMTP. We propose to advance this work by conducting three new lines of investigation. The first will examine neuronal activity during task manipulations of dDNMTP designed to characterize differences in coding properties of neurons in MD, rostral and caudal IL, and Re. We want to learn how information is represented about actions, outcomes, and contextual factors that underlie behavioral choice. Our goal is to elucidate neuronal activity that underlies functions supported by individual nuclei in awake, behaving animals. The second aim will use optogenetic methods to examine the effects of temporarily disrupting MD. MD will be disrupted unilaterally to preserve behavioral function and to allow contralateral mPFC to serve as a control for nonspecific effects of the treatment. We want to learn how MD contributes to the disruptive effects of central thalamic inactivation on neuronal coding in mPFC observed in preliminary studies and behavioral performance observed in earlier reports. Our goal is to understand how momentary changes in MD activity affect mPFC function. The third aim will examine effects of unilateral MD lesions. We will lesion MD before dDNMTP training begins to deprive ipsilesion mPFC of MD input during learning. One control group will receive lesions after training (before recording begins) and another control group will receive sham surgery. We want to ascertain how MD affects neuronal responses in mPFC during learning and how chronic lesions affect the expression of mPFC responses for tasks learned before lesions are made. Our goal is to test the hypotheses that MD plays critical roles shaping responses of mPFC neurons during learning and optimizing information processing in mPFC once behaviors are learned. Beyond its scientific contributions this proposal will enrich opportunities for undergraduate and graduate neuroscience research at UNH providing research opportunities and funds to support students who might otherwise be unable to afford to commit the time required to participate fully in our research program.