Laboratory of Molecular Neurobiology

Welcome to the Laboratory of Molecular Neurobiology at the Boston University School of Medicine. The members of the laboratory are working together as a team under the direction of David H. Farb, PhD, to elucidate the mechanisms by which receptors are regulated, how activation of these receptors modulates neural network activity in vivo and, how this in turn contributes to the onset and progression of memory deficits in age-related neurodegenerative diseases. The laboratory uses a systems neuroscience approach to understanding the functional interactions within neural networks implicated in neurological and psychiatric diseases.  Dr. David Farb and the other members of the Laboratory of Molecular Neurobiology are among the first to use in vivo electrophysiological techniques to advanced our understanding of how drugs modulate neural network activities implicated in memory deficits associated with age-related amnestic mild cognitive impairment (Hippocampus, 2015).  The Laboratory is currently using this same technology combined with ultra fine silicon micro-electrode arrays to identify changes in hippocampal function that underlie cognitive deficits associated with aging and disease and, to assess for the functional neural network correlates associated with effective therapeutics for Alzheimer’s disease.  This research is funded in part by the National Institute on Aging.  The Laboratory of Molecular Neurobiology is part of the Boston University Center for Systems Neuroscience.

The Dancing Place Cells

Double click the image to see Place Cells Dance

In vivo electrophysiological recordings have been used to study neuronal activity and hippocampal dependent learning and memory function since the Nobel Prize winning discovery of “Place Cells” by O’Keefe and Dostrovsky in 1971.  Place cells, are hippocampal pyramidal cells that fire with a greater frequency when an animal is in a specific location.  This activity pattern can be visualized in the video above of the Dancing Place Cells which was made from actual data recordings of hippocampal place cells. These cells establish stable place fields within a given environment and change their firing patterns (“remap”) when the animal is moved to a novel location in a classic remapping paradigm such as that shown in the video below.

Remapping Paradigm Video

The figure below shows the place fields of a rat “remapping” when the animal is moved from a familiar square environment to a novel cylindrical one.  The activity of these place cells is altered by aging and disease.  Place cell activity can also be modulated with drugs (a.k.a., cognitive enhancers).  In recent years, advances in vivo electrophysiology coupled with increased understanding of place cell firing dynamics has opened the door to the use of this technology as a research tool in the preclinical drug discovery process. Pyramidal cells with defined place fields in at least one environment are subsequently analyzed for drug-induced effects on firing rates, spatial correlations across environments, and spatial information content per spike.

Rat ephys 1Plce Cells Ephys 1

Place Fields

The Laboratory of Molecular Neurobiology acquires in vivo electrophysiological data with custom made micro-electrode arrays (such as the one pictured below). The arrays allow us to simultaneously record drug-induced changes in the activity of single place cells and local field potentials from one or more hippocampal subregions (e.g., CA3 and CA1 ) in freely behaving rodents.

Microarray 1

Tetrode 1

The micro-electrode arrays contain tetrodes, comprised of four nichrome micro-electrodes, such as the one pictured above (top) which can be lowered into the hippocampal subregion of interest by turning the screw on a micro drive (bottom).

Micro-electrode Array Construction Video

These tetrodes allow for isolation of individual pyramidal cells based on the proximity of the cell to each of the four wires of the tetrode. The action potentials or “spikes” of individual neurons such as those pictured below are “sorted” manually using Plexon Offline Sorter software as shown below or via semi-automated sorting program for subsequent analysis. Well-isolated cells such as the one pictured below show amplitude differences reflecting their proximity to the four poles of the tetrode.

Tetrode 5

Tetrode 2

Post-hoc differentiation of pyramidal “complex spike” cells (see image A below) and interneurons (see image B below) is facilitated in part by evaluation of auto-correlograms (far left panel), which show distinct patterns of activity, with pyramidal cells showing “complex spikes” characterized by bursts of action potentials immediately following the refractory period.  Pyramidal cells are further differentiated from interneurons by the mean firing rates of the cell and the trough to peak width of their waveforms.  Note that the pyramidal cells also have distinct place fields (far right panel) while the interneurons do not.

A.Complex spike cell clusters

B.Interneurons figure

The laboratory also uses silicon probe arrays which, due to their unique design and flexible layouts permit for recording across strata within a subregion as well as from one or more subregions.

Silicon Probe Array Video