AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

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The broad objective of this research program is to understand how the basal forebrain (BF) cholinergic system (BFC) contributes to specific cognitive operations in anatomically defined circuits. Despite its involvement in cortical activation, attention, and memory, the functional details of the BF are not well understood due to the anatomical complexity of the region. Patients with Alzheimer's disease and related dementias have a significant decrease of acetylcholine (ACh) in the cortex and show pathological changes in cholinergic neurons in the BF. Thus, a complete understanding of its functional organization is warranted. The central hypothesis of our long- standing anatomical studies is that cholinergic projections to the neocortex are not diffuse, but instead are organized into segregated or overlapping pools of projection neurons. While our earlier model dealt with high density projection volumes only, which represent only about 16-30% of cholinergic projection neurons, we now parcel the whole cholinergic space by classifying local projection patterns. According to these studies, cholinergic cells are segregated into topographical sets of clusters projecting to functionally connected cortical targets. In Specific Aim 1 in various BF locations in ChAT::Cre rats, we will apply systematic small injections of AAV coding for the inhibitory DREADD in order to inhibit of the cholinergic projection group within subregions of BF. We will investigate spatio-temporal EEG changes in response to BF cholinergic inhibiton over large parts of the cortex in order to lend support to our idea that the clusters modulate functionally related cortical regions. In Specific Aim 2 using high-density silicon arrays in the orbitofrontal, visual association cortex and the basal forebrain in ChAT::Cre rats during a touchscreen-based visual discrimination task, we will investigate the dynamic pattern of neural activity with millisecond precision to understand cholinergic-related modulatory changes within an anatomically defined neuronal network during specific behavioral epochs, including cue detection, short-term memory, decision making, and behavioral execution. Finally, in Specific Aim 3 we will investigate how activity changes over time in the striatal GABAergic-cholinergic–auditory cortical circuits, during an auditory operant conditioning task, in order to understand how changes between cortical map plasticity and electrophysiological profiles of specific striatal and cholinergic neurons relate to cholinergic-dependent auditory plasticity, learning, memory, and cognitive flexibility. The study of the functional organization of the basalo-cortical network and distinct functions of the cholinergic signal at cellular, network and behavior levels will contribute to better understanding of the dysfunction of attention, decision-making, and memory processes, central to the symptoms of Alzheimer's and other forms of cognitive decline.