There are two broad research programs in our lab. The first, firmly in the realm of ‘Basic Science’, seeks to determine the role(s) that neuromodulators such as acetylcholine, noradrenaline, dopamine and serotonin play in specifying functional connectivity and excitability across the wired circuitry of the brain, and how this dynamic circuit specification supports flexible behavior. To do this, we first study brain structure (anatomy) and then use those anatomical data to develop hypotheses for in vivo study in behaving animals, using methods from physiology, pharmacology, chemistry, and psychophysics. The second program of research in the lab takes a Basic Science approach to understanding the neuropathology underlying Alzheimer’s disease at the transcriptomic, metabolomic, and proteomic levels, with a focus on the female brain and the menopause transition.

Integration of neuromodulation by cortical neurons

Neuromodulators such as dopamine and serotonin dynamically modify neuronal excitability and synaptic strength to wield powerful control over the brain and behavior. Although neuromodulators are often studied individually or pairwise, the joint action of multiple neuromodulators influences input-output mapping, the ‘state’ in which neural processing takes place. At least five subcortical modulatory systems - cholinergic, dopaminergic, histaminergic, noradrenergic, and serotonergic - innervate the cortex. We hypothesize that these inputs are integrated to contribute to a cortical ‘state’ computation. In this project, we evaluate receptor co-expression patterns to investigate the extent to which individual neurons could compute integrated responses to multiple neuromodulators.

Locus Coeruleus encoding of effort.

The locus coeruleus (LC) is a brainstem nucleus that provides the only known noradrenergic input to the mammalian cortex. It has been proposed that LC neurons encode ‘effort’, but it is unclear what this word refers to, in biological terms, in this context. We hypothesize that the LC encodes effort in terms of metabolic cost, based on information from the body, and integrates this cost information with predicted reward information from higher brain centers. We are testing this hypothesis in vivo in behaving animals using neuronal recording in the LC and measurements of noradrenaline release in the cortex.  

The spatial neurochemistry of the aging brain

Late-onset Alzheimer’s disease (LoAD) accounts for >90% of AD cases, and the preclinical phase of LoAD is crucial for diagnosis and intervention. The pathological changes (like amyloid deposition and tau accumulation) that accompany LoAD show a characteristic pattern of emergence and spread across the brain. Some brain regions are affected to a much greater degree than others. The underlying neurochemistry of these spatial patterns, and their biological basis may hold the keys to diagnosis – and, in the case of brain areas that are relatively protected even at late stages of the disease, to protective intervention. In this project, we are developing tools that allow us to deliver within-subject, aligned,  quantitative metabolomic, proteomic, and histologic atlases for peri- and post-menopause female macaques. We measure the levels of thousands of proteins (the proteome) and metabolites (the metabolome) at hundreds of sites across the cortex and cerebellum. In addition, we sample ultrastructural features across these maps to understand synaptic morphology and myelin integrity. In this project, we collaborate with Dr. Pixu Shi and Dr. Michael Lutz to develop novel statistical methods for getting traction on the underlying spatial patterns.

Cholinergic Modulation of Cortical Feedback

Acetylcholine, a neuromodulator often implicated in attention and arousal regulates circuit function by altering neuronal excitability and connectivity. In primary visual cortex (V1), neurons integrate incoming visual information from the eyes, via the thalamus with top-down feedback from other cortical areas (e.g. V2, V4). Previous work in the lab determined the mechanisms and impact of acetylcholine on thalamic input to V1, but it is still unknown how acetylcholine regulates cortical feedback. In this project, we are studying 1) the expression of acetylcholine receptors on cortical feedback axons to V1 and 2) the impact of acetylcholine release on processing of top-down information.

Control of visual input gain by neuromodulation

Controlling the input that arrives at the primary visual cortex (V1) from the eyes is a powerful means for altering the outcome of all subsequent processing of visual information. While this is widely acknowledged to be a critical process, debate continues regarding the means by which this gain control is achieved. In particular, the control of sensory processing by behavioral and cognitive states (such as attention) almost certainly arises, at least in part, from circuits outside the cortex. This control of cortical circuits by subcortical nuclei is poorly understood. Previous anatomical data tell us that modulation by the subcortical neuromodulatory systems is strongly directed toward the site of visual input to cortex. This localization positions neuromodulation to control the extent to which information from the eyes gets processed, and therefore whether and how it is perceived. In this project, we causally manipulate this modulatory control during active vision, and determine the resulting effects on both neural responses and behavior.

Acetylcholine and visual attention

It has been proposed that the neuromodulator acetylcholine is a critical component in the mechanism for attention but there is scarce evidence that the cholinergic system actually has the requisite specificity to play this role. In this project, we are measuring both neural activity and the concentration, timing and spatial extent of acetylcholine release in vivo while animals perform a visual attention task.