1989 — 1991 |
Brown, Thomas H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Amygdaloid Long-Term Potentiation &Pavlovian Condition
The working hypothesis of this proposal is that certain forms of learning reflect changes in the strengths of synaptic connections between the critically-involved neurons. The synaptic hypothesis for learning has not yet been adequately tested in mammals, although there is plenty of indirect evidence. The phenomenon of long-term synaptic potentiation (LTP), first discovered in the hippocampus, is widely touted as the most promising candidate synaptic substrate for rapid forms of learning In vertebrates. LTP was recently discovered to occur in the amygdala, another temporal lobe brain structure. The amygdala and hippocampus have repeatedly been implicated in various mnemonic functions in man and other animals. Knowledge of the cellular neurophysiology of the hippocampus and the mechanisms underlying hippocampal LTP is beginning to emerge, but comparable information does not exist for the amygdala. The goal of this proposal is to understand the mechanisms underlying amygdaloid LTP at the level of cellular neurophysiology and to test the idea that this form of synaptic plasticity is in fact involved in a particular type of rapid Pavlovian conditioning. The mechanisms will be explored using cultured and acute amygdala brain slices (two preparations that this laboratory has been developing) in conjunction with high-resolution visualization and neurophysiological techniques (whose application to brain slices this laboratory has also helped to pioneer). The knowledge gained from these in vitro systems about the underlying mechanisms will be used in in vivo experiments designed to test the hypothesis that amygdaloid LTP participates in aspects of rapid fear conditioning. The information that will be provided is relevant not only to the synaptic hypothesis for learning. The amygdala has major significance for neurology and psychiatry. Further understanding of the cellular neurophysiology and pharmacology of this structure will be relevant to the cause or treatment of numerous human neuropsychological disorders--possibly including major and minor mood disorders, memory impairments, sexual dysfunctions, epilepsy and certain violent behaviors.
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1993 |
Brown, Thomas H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Microphysiology of Hippocampal Mossy Fiber Synapses
The hippocampus is one of the most extensively studied brain regions. The popularity of this structure derives from four considerations-it is important in major clinical disorders; its architecture is convenient, relative to other cortical areas, for experimental analysis; it appears to play an essential role in "cognitive" forms of learning and/or memory; and its synapses exhibit long-term potentiation (LTP), currently the leading candidate mechanism for rapid learning in mammals. Within the hippocampus, the neurophysiology of synapses in region CA3 region is the least understood. The granule cells of the dentate gyrus provide an important synaptic input to region CA3. The granule cell's mossy-fiber (mf) synaptic input is unusual and interesting for several reasons-they are among the largest synapses in the brain; they contain dynorphin and high concentrations of zinc; and they display a form of LTP that is different from the kind that is most often studied in other regions of the hippocampus and neocortex. The induction of mf LTP is not dependent on activation of N-methyl-d-aspartate (NMDA) receptors. We now know that NMDA receptor-independent LTP is not unique to the mf synapses, but also exists in synapses of other brain regions, such las the amygdala. The mf synapses offer a number of unique experimental advantages, which we will develop and exploit. State-of-the-art experimental and analytical methods will be used to examine the microphysiology of mf synapses and to test several hypotheses about the mechanisms underlying mf LTP induction and expression. The methods include whole-cell recordings of synaptic currents; quantal analysis; optical measurements of synaptic microstructure, calcium transients, and vesicle recycling; and compartmental modelling of mf synapses and CA3 pyramidal neurons. The results will provide a firm understanding of synaptic signalling and plasticity in the mf synapses, furnishing a key piece in the larger puzzle of how the hippocampal circuitry processes and stores information. This knowledge will be relevant to other brain regions, where comparable experiments would be impracticable.
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1994 — 1995 |
Brown, Thomas H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Microphysiology of Hippocampal Mossy-Fiber Synapses |
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1996 — 1999 |
Brown, Thomas H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Amygdala/Perirhinal System--Synapses and Neurons |
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1998 — 2002 |
Brown, Thomas H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Learning and Response Circuitry in Aversive Conditioning
DESCRIPTION (Adapted from applicant's abstract): Emotions play a tremendous role in our lives - creating priorities, shaping values, and guiding our most important choices. Recent studies demonstrate that learning and memory in humans is much more profoundly affected by emotion than was previously assumed. The long-term goal is to understand how the amygdala and related brain regions are involved in emotional learning and memory. This requires elucidating the necessary and modulatory structures involved in emotional learning. The model preparation for studying aversive Pavlovian learning entails conditioned enhancement of the rat eyeblink reflex. The short-latency (R1) electromyographic component of the blink reflex offers several advantages as an index of emotional learning. The proposed methods combine neurophysiology, neuroanatomy, behavior and computational modeling. A general working hypothesis has been developed, an associated computational model, and a behavioral paradigm for evaluating the role of the amygdala and perirhinal cortex in forming associations between a conditioned stimulus (CS) and an unconditioned stimulus (US) and for encoding the CS-US interval during aversive conditioning. The computational model is the first to show how certain temporal aspects of associative learning emerge from the cellular neurobiology and circuitry. The approach allows vertical integration, traversing several levels of organization - from synapses to circuits to behavior. The model serves as the current hypothesis and also as the theoretical glue that binds information within and among levels and helps us understand and test various proposed hypotheses. In pursuit of the goal of vertical integration, the system selected for study enables one to go back and forth between in vitro and in vivo analysis, and the technology to do so is available (although the present proposal is concerned with in vivo studies). One goal is to demystify some of the psychological components of certain disorders by understanding the circuitry involved in emotional learning and to develop testable hypothesis for explaining biological changes that occur during stressful situations. The information and technology should be relevant to insights into, and treatment of, both psychiatric and neurological disorders (anxiety, stress, panic, cognitive impairment, blepharospasm, and epilepsy). By design, the approach is extendible into aging-related problems.
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2000 |
Brown, Thomas H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Amygdala--Perirhinal System: Synapses and Neurons
DESCRIPTION (Adapted from Applicant's Abstract): The perirhinal cortex (PR) and adjacent lateral amygdala (LA) are implicated in learning and emotion as well as certain disorders such as Alzheimer's disease, epilepsy, and schizophrenia. To understand the roles of these brain structures in learning and emotion, and the manner in which they might become compromised during aging or in disease states, one must know more about the properties of their neurons and synaptic interconnections. Preliminary data suggested a specific and testable working hypothesis about how the cellular and synaptic properties of neurons in PR and LA might combine to produce aspects of the emotional learning in which these brain regions are thought to participate. To evaluate and develop further the working hypothesis requires (i) collection of the requisite physiological and anatomical data describing the properties of PR and LA neurons; (ii) physiological and pharmacological characterization of their synaptic interconnections; and (iii) incorporation of these data into computational models. The experimental and modeling results will test certain cellular- and circuit-level mechanisms implicit in the working hypothesis. It is expected that the principles revealed in these computational models will generalize to other brain regions as well. This laboratory has already applied several useful and powerful methods to rat brain slices containing PR and LA-- including whole-cell recordings from visually preselected neurons, confocal microscopy, and serial anatomical reconstructions of recorded cells. These and additional proposed methodological advances will enable collection of the experimental data required to evaluate and extend the working hypothesis. The data will also furnish a quantitative baseline for evaluating aging-related neuronal changes in PR and LA, changes of the kind that could explain certain aging-related alterations in learning, memory, and mood seen in humans. Ultimately, the information gained by these studies should be pertinent to the prevention and/or treatment of age- or disease-related mental dysfunctions, including Alzheimer's disease, epilepsy, and schizophrenia.
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2001 — 2005 |
Brown, Thomas Huntington |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Amygdala-Perihinal System: Synapses and Neurons |
1 |
2003 — 2007 |
Brown, Thomas Huntington |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Learning and Response Circuity in Aversive Conditioning
DESCRIPTION (provided by applicant): Three medial-temporal-lobe (MTL) structures--perirhinal cortex (PR), amygdala (AM), and hippocampus (HC)--are known to be critical for emotional and cognitive aspects of animal and human learning and memory. All three are also severely compromised in Alzheimer's disease (AD). Here we combine methods of behavioral and computational neuroscience to elucidate the manner in which performance declines within rat MTL circuits as a function of aging. Special focus is on PR/AM function because of the recognized importance of these two structures in emotional and cognitive aspects of learning and memory; because almost nothing is known about the functional consequences of aging associated changes in the cellular neurobiology of these structures, which we study in a separate but parallel in vitro research project; and because PR is one of the earliest brain regions to develop neurofibrillary tangles, which are characteristic of Alzheimer's disease. The role of PR/AM circuitry in aging-related performance decline has never been addressed. Our battery of conditioning procedures is designed to increase the performance demand on PR/AM circuits. I expect to create a set of more sensitive and circuit-specific Pavlovian measures of aging-related performance decline. The test battery will be combined with neurobiological manipulations to get a better understanding of normal PR function and its changes during aging. This theory-driven research should impact in three directions. First, it will furnish critical experimental data regarding normal PR/AM function that will test and/or be incorporated into our computational model of the neurophysiology of PR/AM-dependent fear conditioning. This is the only such model and we plan to develop it further. Second, the tests can be used to "time stamp" circuit-specific changes during aging. This information is needed to detect and understand the temporal and causal relationship between particular changes in cognition and specific modifications in the underlying neurobiology. Third, the overall results will furnish a better basis for evaluating therapeutic treatment effects. Based on the "calcium dysregulation" hypothesis for cognitive aging, a treatment strategy we shall explore involves pharmacologically altering a calcium-dependent potassium current that is thought to be altered in opposite directions by conditioning and aging.
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