Research

The research in NECO lab mostly concerns neurochemistry of cognitive processes, specifically those involved in attention and executive functions. These mental processes are critical for learning, acquiring and assimilating knowledge through experience, and applying this knowledge to act sensibly in changing environments. Cognitive abilities decline in patients suffering from major neuropsychiatric and age-related neurodegenerative disorders, impacting individuals’ ability to perform activities of daily living, work productively and function socially. Our research program is motivated by the goal of achieving a better understanding of the underlying neural causes of the cognitive dysfunction associated with these pathologies. This research is important because identifying the causal mechanisms along with potential biomarkers may allow us to design interventions to treat cognitive disorders. Our research involves the use of animals (rodents) that model either normative behavior or behavioral/cognitive features ofa pathology.We aim to gain an integrative perspective on brain-behavior relationships by utilizing diverse neuroscientific techniques. Some of the techniques routinely used in our lab are in vivo extracellular electrochemical recordings to monitor real time changes in synaptic transmission, operant paradigms to assess cognitive functions in rodents, and genetic and biochemical approaches including the use of transgenic mice and virus-based gene manipulations, immunohistochemistry, cell imaging, western blotting and PCR. Currently,we are pursuing two major lines of research.The first concerns neurochemistry of age-related changes in attentional capacities. The second focuses on neuromodulation of fronto-executive functions.

Attentional capacities in normal and pathological aging

 Attention describes a set of cognitive processes that support the ability to selectively concentrate on one aspect of the environment while ignoring others. These selective processes facilitate our ability to encode, organize, store, revise, and retrieve information. Although individual differences in cognitive aging have been observed, it is not clear why only certain individuals show a marked decline in attentional capacities, and eventually develop age-related dementias and Alzheimer’s disease (AD). As aging is a well-recognized risk factor for AD, understanding the neurochemical signaling mechanisms underlying decline in attentional capacities in normal and pathological aging remains an elusive goal. By studying the relationship between brain neurochemical signaling messengers and behavior in normal and pathological aging, we can delineate fundamental mechanisms that contribute to dysfunctional cognitive abilities.

Much of our previous research focused on determining the contribution of acetylcholine in attention. We demonstrated that cortical cholinergic signaling operates in multiple modes to encode information pertaining to cues guiding behavior,to optimize signal detection and to maintain sensory arousal. Our current research seeks to understand how cortical cholinergic signaling and attentional capacities change in normal and pathological aging, and what cellular mechanisms regulate cholinergic function in aging. A major focus of this research is to determine the role of cholinotrophic protein nerve growth factor signaling in cholinergic modulation of attention in aging and AD. We are also exploring prefrontal mechanisms of age-related cognitive and cholinergic compensation in aging. These studies are driven by the notion that attempts to cope with functional age-related changes may go awry due to poor cognitive reserve, and that aberrations in cholinergic compensation may lead to decline in attentional capacities. Additionally, we are investigating how life-long cognitive activity affects cognitive reserve capacity and performance variability in aging, and whether these changes involve alterations in cholinotrophic signaling.

 

Corticostriatal circuits and executive functions

Adaptive cognitive control is necessary to act flexibly in changing environments and to maintain cognitive operations in accordance with ongoing task demands. These executive processes are critical to regulate motivation to achieve goals. The integrity of corticostriatal circuits is critical for cognitive flexibility and these circuits are compromised in neuropsychiatric disorders.  Our research explores mechanisms that regulate the dynamics of these circuits and that influence cognitive control processes.

 Neurotrophins regulate synaptic plasticity and are implicated in neuropsychiatric disorders such as schizophrenia and addiction. Therefore, understanding how these growth-promoting proteins modulate executive processes will provide important information on fundamental mechanisms underlying cognitive deficits in these disorders. We recently demonstrated that local application of brain-derived neurotrophic factor (BDNF) into the dorsal striatum facilitates strategy shifting in mice. Moreover, striatal BDNF-mediated cognitive enhancement primarily required activation of presynaptic corticostriatal glutamate terminals via trkB receptors. Currently we are exploring how endogenous BDNF signaling in discrete corticostriatal circuits alter decision-making and whether these effects involve reciprocal glutamatergic-monoaminergic interactions in the dorsal striatum. Another major ongoing project in the lab concerns the effects of   chronic exposure of psychostimulants on cognitive control and flexible decision-making. We are investigating whether alterations in cognitive flexibility during nicotine dependence are linked to aberrations in corticostriatal BDNF mechanisms and dysregulated glutamate signaling. In a related study, our lab is exploring how repeated cocaine exposure produces neuroadaptive changes in the striatal glutamatergic signaling and whether these effects are linked to maladaptive decision-making.

 

Collaborators

Debra Bangasser, Ph.D. (Temple University)

Lisa Briand, Ph.D. (Temple University)

Thomas J. Gould, Ph.D. (Penn State University)

Scott M. Rawls, Ph.D. (Temple University School of Medicine)

David L. Turner, Ph.D. (University of Michigan)

Ellen M. Unterwald, Ph.D. (Temple University School of Medicine)

Angela J. Yu, Ph.D. (University of California, San Diego)

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