Research

Systems Neuroscience of Cognition and Dementia Laboratory

Spatial memory, our ability to form a mental map of our surroundings, weakens with normal aging and is one of the earliest and most severely affected cognitive domains in Alzheimer’s disease (AD), producing hallmark symptoms of confusion, disorientation, and getting lost even in familiar places. The Laboratory for Systems Neuroscience of Cognition and Dementia, directed by Dr. Abid Hussaini at the Center for Dementia Research at the Nathan Kline Institute, studies the entorhinal cortex, hippocampus, and locus coeruleus (LC), three interconnected regions among the earliest affected in aging and AD, to determine how neuronal dysfunction in each region drives cognitive decline.

The lab specializes in single-unit electrophysiological recording from freely behaving and head-fixed mice navigating virtual reality environments, tracking the activity of grid cells, place cells, border cells, and head-direction cells in the entorhinal cortex and hippocampus, and extending this approach to the LC, a brainstem region now recognized as one of the earliest sites of tau accumulation in AD, appearing decades before pathology reaches the entorhinal cortex. Using AD mouse models expressing amyloid-beta and tau pathology (including App and MAPT knock-in mice and region-specific EC-App and EC-tau models), combined with optogenetic and chemogenetic manipulation of neuronal firing, the lab has shown that entorhinal cortex hyperactivity drives tau propagation and that attenuating this hyperactivity reduces amyloid and tau pathology in the hippocampus. Building on this, the lab is now examining whether LC hyperexcitability similarly disrupts downstream hippocampal firing, network oscillations, and memory, and whether restoring normal LC activity can reverse these deficits. The lab has also developed open-source computational tools, including a novel optimal-transport metric for quantifying representational drift in spatial-coding neurons, to support rigorous analysis of neural circuit dysfunction.

In summary, the lab aims to identify the earliest circuit-level dysfunction, from locus coeruleus to entorhinal cortex to hippocampus, that drives cognitive decline in AD, and to develop strategies to reverse it.

Research Interests:

Dr. Hussaini’s research addresses how the brain forms and maintains spatial memory, and how this process breaks down in aging and Alzheimer’s disease. His work centers on the entorhinal cortex, one of the first regions affected in AD, and its downstream hippocampal targets, using in vivo electrophysiology to identify which cell types are selectively vulnerable to disease. His studies have shown that tau pathology disrupts grid cells specifically while sparing other cells in the same circuit, establishing cell-type-specific vulnerability as a key feature of early AD pathophysiology.

A second focus is the relationship between neuronal hyperactivity and disease progression along the entorhinal cortex to hippocampus pathway. Building on findings that amyloid-beta accumulation drives aberrant network hyperactivity and disrupted oscillatory rhythms, the lab has demonstrated that this hyperactivity actively drives tau propagation, and that chemogenetically suppressing it reduces both amyloid and tau burden, pointing to neuronal activity itself as a therapeutic target.

A newer, related direction extends this framework to the locus coeruleus. Since tau pathology has been shown to accumulate in the LC before it appears in the entorhinal cortex, Dr. Hussaini’s lab is now recording simultaneously from the LC and hippocampal CA1 in freely behaving mice to test whether LC hyperexcitability itself disrupts downstream firing patterns, network oscillations, and spatial memory performance. Using optogenetic stimulation to drive LC hyperactivity and chemogenetic (DREADD-based) approaches to suppress it, the lab is testing whether normalizing LC firing restores hippocampal place cell coherence, stability, and memory function, applying machine-learning-based decoding methods (developed in collaboration with computational neuroscience colleagues) to detect these circuit changes with greater sensitivity than traditional measures.

Education
B.Sc. (Env. Science), Bangalore University, Bangalore, Karnataka, India
M.Sc. (Toxicology), University of Madras, Chennai, India
Ph.D. (Neurobiology), Freie Universität Berlin, Berlin, Germany

Postdoctoral Training
Neuroscience, Columbia University, New York, NY, with Dr. Eric Kandel

Awards and Honors
2020    Alzheimer’s Association Research Award, Alzheimer’s Association, USA
2019    BrightFocus Foundation award, USA
2015    New Investigator Award from the Alzheimer’s Association, Alzheimer’s Association, USA
2004    Graduate School Scholarship from Graduiertenkolleg 837 ‘Functional Insect Science’, German Research Council (DFG), Germany