Faculty Profiles Miller School of Medicine

40 Years of Cellular and Molecular Neurobiology PMC

It is our brain that makes us different from animals, and while have learned much about the fundamental mechanisms upon which all nervous systems function, we have a long way to go to fully understand the basis of learning, memory, emotions, and human behavior. I hope that over the next 40 years, Cellular and Molecular Neurobiology will remain at the forefront in publishing research advances that will elucidate how our brains work. Much of this work involves understanding the role of brain connectivity in producing the computations apparent in task-driven brain activity patterns and behavior. This facilitates theoretical understanding of cognitive processes as they are generated by brain network interactions, providing insights into both natural and artificial intelligence. We achieve this using a variety of techniques, applying network science, computational modeling, and machine learning approaches to data collected from the human brain (with fMRI, MEG, EEG, diffusion MRI, and behavioral measures) and neural network simulations. We use imaging approaches to acquire large-scale recordings of neural activity during behavior, focusing on deep-brain areas implicated in neurological and psychiatric diseases, such as striatum.

Developing neurons integrate into functional circuits through a series of cell recognition events, which include neuronal sorting, axon and dendrite patterning, synaptic selection, among others. Our research focuses on cell-surface recognition molecules that mediate interactions between neurons to discriminate and select appropriate targets in the developing brain. Additionally, we seek to uncover novel mechanisms of neural recognition that lead to brain connectivity defects in humans. To explore the broader roles for cell recognition molecules and their pivotal function in neural circuit development, our lab takes advantage of a battery of modern laboratory techniques. These approaches include animal and stem cell disease modeling, as well as next-generation sequencing and CRISPR/Cas9 gene editing.

Find out how NIMH engages a range of stakeholder organizations as part of its efforts to ensure the greatest public health impact of the research we support. For lab information and more, see Dr. Pinto’s faculty profile and laboratory website.

Harvard’s diverse neuroscience community — hundreds of basic researchers and physician-scientists, are engaged in the process of discovery across campuses and disciplines in Cambridge and the Greater Boston Area. Three major nodes are the Department of Neurobiology at Harvard Medical School, the Center for Brain Science (CBS) at the Faculty of Arts and Sciences in Cambridge and the F.M. Sex hormonal releases have a significant effect on sexual dimorphisms (phenotypic differentiation of sexual characteristics) of the brain. Recent studies seem to suggest that regulating these dimorphisms has implications for understanding normal and abnormal brain function. Sexual dimorphisms may be significantly influenced by sex-based brain gene expression which varies from species to species.

Stellwagen et al. review the new appreciation for astrocytes and microglia in contributing to adaptive and mal-adaptive responses. Recently the concept of ‘membrane-less’ organelles has emerged in many areas of cell biology, where protein assemblies can be driven by numerous weak multi-valent interactions through intrinsically disordered protein domains. Feng et al. review evidence for the presence of these novel protein-phases in both the pre-synaptic and post-synaptic compartments. A key but relatively recently appreciated aspect of synapse function is the constant need for fuel to keep the machinery running. Rossi and Pekkurnaz review how mitochondria at synapses are able to change their behavior in response to changes in energetic requirements. How neurons form synapses with the correct partners and how synapses are maintained throughout lifetime of an organism remain the long-standing questions.

Charles Heckman LabInvestigating the mechanisms of motor output the spinal cord in both normal and disease states

Using a combination of optical, electrophysiological and molecular approaches, we are examining the factors governing neurodegeneration in PD and its network consequences, primarily in the striatum. This work has led to a Phase III neuroprotection clinical trial for early stage PD and a drug development program targeting a sub-class of calcium channels. The second topic area is network dysfunction in Huntington’s disease (HD). Using the same set of approaches, we are exploring striatal and pallidal dysfunction in genetic models of HD, again with the aim of identifying novel drug targets. The third topic area is striatal dysfunction in schizophrenia, with a particular interest in striatal adaptations to neuroleptic treatment.

Sandra Rieger, Ph.D.

• Understanding mal-adaptive changes in synapse function in response to chronic exposure to drugs of abuse has been an important goal that lies at the intersection of synapse biology and addiction research.
• Dr Ryan’s lab has pioneered the development and use of quantitative optical tools to interrogate nerve terminal function.
• We utilize multiple experimental approaches including electrophysiology, 2-photon imaging, anatomical and molecular profiling, and viral vector-based techniques including optogenetics, pharmacogenetics and knockdown of synaptic receptors and ion channels.
• Sex hormonal releases have a significant effect on sexual dimorphisms (phenotypic differentiation of sexual characteristics) of the brain.
• Three major nodes are the Department of Neurobiology at Harvard Medical School, the Center for Brain Science (CBS) at the Faculty of Arts and Sciences in Cambridge and the F.M.

Kurshan and Shen emphasize the progress on the molecular composition and dynamics in pre-synaptic and post-synaptic compartments, and highlight the roles of γ-neurexin, a newly discovered short and conserved isoform of neurexin, in synapse formation in Caenorhabditis elegans. This γ-neurexin lacks trans-synaptic binding domains, and is capable to amplify presynaptic assembly pathways through its intracellular PDZ-binding motif. Apóstolo and de Wit cover new findings revealing the compartmentalized distribution and function of various cell surface molecules in mammalian brain. They further discuss how numerous glial-derive factors interact with neuronal cell surface proteins, and how secreted proteins, such as complement proteins C1ql2 and C1ql3, modulate excitatory synapse connections and function.

Identifying fundamental principles of cellular recognition in wiring circuits contributes to our understanding of neurological disorders and how neuronal dysfunction arises from aberrations during development of the human brain. Research in my laboratory centers on the molecular and cellular mechanisms that control the formation and modification of dendritic spines in the mammalian brain. These mechanisms underlie the normal development and plasticity of the brain, and contribute to higher brain functions, including cognitive, social, and communication behavior. However, when these mechanisms go awry, they lead to mental and neurological disorders. Our analysis integrates multiple organizational levels, from molecular, cellular, circuit, and rodent models, to human subjects. The ultimate goal of these studies is to develop therapeutic approaches to prevent or reverse neuropsychiatric disorders, by targeting mechanisms that control dendritic spines and synapses.

Our research has already led us to the development of investigational medicines that are currently in clinical trials. Our laboratory utilizes a one-of-a-kind bio-bank that collects not only tissue and blood from tumors for research, but, unlike other such facilities, also includes live cells that provide RNA (ribonucleic acid) that is essential to research. Our goal is to discover novel synaptic mechanisms that are of physiological relevance, but may also provide original insights for the pathogenesis of neurological diseases such as epilepsy and neurodevelopmental disorders, which often target the hippocampus. Once they knew the peptides had adhered to the LNPs, the researchers then had to determine whether or not the peptide-functionalized LNPs (pLNPs) actually reached the intended targets in animal models. This represents an important advance in delivering mRNA to the cell types that would be key in treating neurodegenerative diseases; any such treatments molecular neuroscience laboratory will need to ensure that mRNA arrives at the correct location. Previous work by the same researchers proved that LNPs can cross the BBB and deliver mRNA to the brain, but did not attempt to control which cells the LNPs targeted.