Brain Ponderings podcast with Mark Mattson

Professor Karl Friston of University College London has made major technical advances and discoveries that are revealing how the brain processes information in ways that result in appropriate behaviors.  He talks about two brain imaging methods – positron emission tomography and functional magnetic resonance imaging – and how they have advanced an understanding of how neuronal networks are organized in a functionally integrated manner. He has used brain imaging to elucidate what goes wrong in schizophrenia. More recently he developed a theory called active inference or ‘the free energy principle’ which provides a mathematical framework for how the brain processes information. This theory promises to be a valuable tool in the fields of neuroscience and artificial intelligence.

Why are some people susceptible to becoming addicted to a drug or developing severe depression, while others are not? Professor Eric Nestler of Mount Sinai School of Medicine talks about research suggesting one explanation: epigenetic alterations – enduring changes in the activation of certain genes – in neurons results in long-lasting changes in structure and function of neuronal networks. In addiction, repeated drug exposure results in excessive release of dopamine onto ‘medium spiny neurons’ in a brain region called the nucleus accumbens. Over time this leads to molecular changes in proteins called histones in the nucleus. The histones are part of molecular structures called chromatin upon which DNA is wound. By changing the structure of the chromatin the expression of genes on the associated DNA is altered in ways that contribute to addiction. Dr. Nestler’s laboratory is also elucidating the roles  epigenetic molecular alterations that occur as a result of chronic stress contribute to depression.

I talk with Professor Stephen Cunnane of Sherbrooke University about emerging evidence that ketones can protect neurons in the brain against dysfunction and degeneration during aging.  The ability of neurons to utilize glucose as an energy source is impaired in Alzheimer’s disease, but the neurons can still utilize ketones. In addition, ketones can activate genes that encode proteins that help the neuron withstand stress and form new synaptic connections.

Glioblastoma is a highly malignant and almost always fatal brain cancer. Neuro-oncologist Justin Lathia of the Cleveland Clinic shares his knowledge and research discoveries on what makes glioblastomas so nasty. The cancer cells within the tumor vary greatly in their genetic abnormalities and sensitivities to chemotherapy and radiation Particularly resistant to treatment are glioblastoma stem cells. These cancer cells interact with other cells in the brain in ways that enable them to flourish and to evade the immune system. Knowledge of these mechanisms is providing new avenues for developing effective treatments.

Professor Jeffrey Macklis of Harvard University describes how different types of neurons in the cerebral cortex arise from progenitor [stem] cells and how those neurons grow and make highly specific connections with other neurons.. His findings in animal models have shown that it is possible to replace neurons lost as a result of traumatic injury or neurodegenerative conditions such as ALS and Alzheimer’s disease.

Professor James Knierim of Johns Hopkins University describes how the brain processes visual information in ways that enable us to accurately navigate through our environment and remember what we experience during our journeys. Discoveries made during the past several decades have revealed that neuronal circuits in two intimately connected brain regions – the entorhinal cortex and hippocampus – are key to the ‘brain’s GPS’ and the generation of ‘cognitive maps’. These neuronal circuits are of fundamental importance in learning and memory and are the first to degenerate in Alzheimer’s disease.

Professor Hey-Kyoung Lee of Johns Hopkins University describes how the brain’s neuronal networks reorganize themselves in response to sensory deficits such as blindness and deafness. In blind people neuronal circuits in the visual cortex become responsive to sounds and touch. By recording electrical activity in individual neurons in the visual cortex of mice kept in complete darkness she discovered that some synaptic connections between neurons become stronger. Interestingly, temporary deafening of mice results in increased strength of synapses in the visual cortex. The latter finding suggests that it may be possible to enhance recovery of brain function after an injury to one sensory system by temporarily depriving input from a different sensory system.

Professor Jonathan Kipnis of the Washington University School of Medicine talks about the brain’s immune system. He and is students and postdocs have provided evidence that cells of the immune system are critical for protecting neurons of the brain and spinal cord against traumatic injury, and that ‘protective autoimmunity’ can also be beneficial for the brain in animal models of multiple sclerosis and autism. Their discoveries have also revealed important roles for a type of T lymphocyte in learning and memory, anxiety, and social behaviors. Dr. Kipnis recently discovered that the brain has its own lymphatic system that functions as a drainage system through which molecular waste is removed. This lymphatic system may become clogged during aging which may contribute to the accumulation of toxic amyloid in the brain in Alzheimer’s disease. He discusses the implications of his research findings for the prevention and treatment of neurological disorders.

What determines whether we make good or bad decisions? Professor Michael Platt of the University of Pennsylvania is a biological anthropologist, neuroscientist, and neuroeconomist whose research has elucidated the neuronal networks involved in decision-making. By recording electrical activity in neurons of non-human primates while they are making decisions Platt has shown that circuits in prefrontal cortex and adjacent cingulate gyrus are particularly important in decision-making. More recently he has been applying his knowledge of the neurobiology of decision-making to help businesses enhance their productivity.

Sarkis Mazmanian is a professor of microbiology at the California Institute of Technology. Research in his laboratory has provided evidence that bacteria in the intestines play important roles in the normal development and function of the immune and nervous systems. His findings suggest roles for certain gut bacteria in the pathogenesis of autoimmune disorders and Parkinson’s disease. He discovered that one species of gut bacteria can improve immune function and can ameliorate behavioral abnormalities in an animal model of autism.