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Molecular and Integrative Neursociences Department
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Researchers in the Molecular and Integrative Neursociences Department explore the function of the normal and diseased brain and establish the fundamental
mechanisms by which the environment and genes lead to disorders. Some scientists study the mechanisms of neuronal synaptic communication to determine
the difference between normal signaling and signaling in AIDS patients or those who are dependent on alcohol, marijuana, cocaine, morphine, tobacco, or other
drugs. Other researchers focus on various aspects of the brain's chemicals, molecules, or cells to achieve a better understanding of how to devise
effective treatments for these conditions. One investigator, for instance, tested a novel HIV protease inhibitor that was developed at TSRI and demonstrated
in preclinical studies that it could protect against the ravages of AIDS.
The department has a large program to study the effect of HIV on the brain, a debilitating but often overlooked
aspect of the disease. One quarter to one third of all AIDS patients suffer from some form of central nervous system disorder during the course of their
infection, ranging from minor cognitive and motor disorders to severe dementia, symptoms collectively known as neuroAIDS. These problems are the direct result of
the inflammation brought on by immune cells coursing through the brain. This inflammation interferes with neuron signaling, slowing down the processes
within the cerebral cortex, the part of the brain responsible for higher brain functions such as thought, sensation, voluntary muscle movement, reasoning, and
memory.
The Scripps NeuroAIDS Preclinical Studies Center, funded recently through a $10-million grant from the National
Institute of Mental Health, brings together scientists from throughout the institute to further research the cause, prevention, and treatment of HIV infection in
the brain.
Other research groups within the department conduct programs that investigate how viruses get into the brain and
how they cause disease. One group studies the mechanisms of immune system interactions that mediate the pathologic effects of viral infection in the
central nervous system. Another group has examined the synergy between one drug of abuse (methamphetamine) and AIDS, demonstrating how the former can
act synergistically to worsen the brain-related effects of the disease.
Investigators in the department also study a number of other viruses. Two researchers were responsible for identifying and mapping the cell receptor
for Lassa fever virus, the major cause of hemorrhagic fever. One of these scientists also made a major contribution to the field of virology by proposing
"molecular mimicry" as a mechanism that contributes to autoimmune diseases like diabetes and multiple sclerosis--a mechanism now substantiated and quoted by the
biomedical community.
Another investigator looks at how brain injury occurs as a result of viral infections
by looking at the host immune response to the infection and the role played
by host cells, receptors, and signaling molecules in brain pathogenesis--findings
that have set the stage for potential therapeutic approaches in certain neurodegenerative
diseases. Another group studies the ability of hepatitis virus to remove myelin,
the sheath surrounding nerve fibers, as an experimental model of human multiple
sclerosis.
One group in the department asks whether new tools can be developed to fight some of these viruses, studying the molecular and immune
mechanisms involved in viral pathogenesis and antiviral immunity, and developing approaches to vaccinate against viral diseases using DNA.
For more than 20 years, TSRI's alcohol research center has been investigating the long-term effects of alcohol
on the brain. Recently, the National Institute on Alcohol Abuse and Alcoholism funded a multi-year, multi-center consortium headed by researchers at TSRI to
identify the molecular basis of alcoholism. The Integrative Neuroscience Initiative on Alcoholism aims to address the basic science of alcoholism and to
establish a platform upon which future treatments can be built.
One group in the department studies the role of genetic factors and their interactions with brain
motivational circuits in alcoholism. Understanding motivational circuits is critical to understanding drug abuse and the brain. Many drugs act as natural
neural transmitters, turning on what is known as the reward system within the brain and making the user feel good. Drug dependence often develops because of
these rewards. Another group demonstrated directly, for the first time, a novel mechanism by which alcohol increases inhibitory neurotransmission in
virtually all neurons of the central amygdala, a brain region known to be involved in the rewarding effects of alcohol.
Several researchers, in fact, study the basis of this system of reward and motivation as it relates to drug abuse. They have
conceptualized drug dependence as a break with the normal balance in the brain, referred to as homeostasis. Under homeostasis, the body maintains certain
physiological parameters, like blood pressure, glucose and oxygen levels, or body temperature within a desired range--the same way a building's thermostat
turns the heat or the air conditioning on or off as required to maintain one temperature. The balance becomes "allostatic" when these adjusting systems
become progressively taxed from substance abuse and the body loses the ability to maintain balance within acceptable normal ranges. This allostatic balance or
state results in overt stability but at a potentially pathologically altered set point.
Other topics of investigation in the department include the interaction of drugs and the neurotransmitters they
affect in altering ognition; brain motivational circuits and their connections in drug craving and relapse; the neurological basis of attention and arousal,
and the relevance of these mechanisms to human diseases such as attention deficit disorder and schizophrenia; interactions of drugs of abuse, such as amphetamines and
alcohol, with the neuropeptide systems in the brain's reward pathways; and the basis of reward in methamphetamine abuse.
Many investigators in the department are interested in the effect of the body's own substances on the brain. One group studies the role of
calcium signaling in regulating neuronal functioning and development, particularly as it relates to the presence of cannanbinoid-containing drugs
like marijuana. Another group examines the role of neurotransmitters and cytokines in disorders of sleep and waking. The role and mechanisms of action
of cytokines and chemokines in the brain in inflammatory states are under investigation, as are the molecular and cellular correlates of changes in
cognition, long-term memory, and emotional states. And another group has verified that "opioid" peptides act on central neurons in most brain regions by a novel
disinhibitory mechanism--selectively inhibiting inhibitory interneurons (they block the blockers).
Understanding the link between the physiology of the brain and behavior is a key goal of all the investigators in
the Molecular and Integrative Neursociences Department, as is turning these basic observations into useful therapies for degenerative diseases, emotional disorders, and drug
addiction.
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