2007 — 2008 |
Heck, Detlef H. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Use of Dynamic Photostimulation to Investigate Synaptic Integration in Vitro @ University of Tennessee Health Sci Ctr
[unreadable] DESCRIPTION (provided by applicant): The main purpose of this project is to establish and test a new method that will expand the use of the vitro slice preparations to study spatio-temporal aspects of synaptic integration and the effects of ongoing network activity on neuronal computation. Acute slices are a useful in vitro model for the investigation of nervous system function. However, a significant pitfall is the lack of background neuronal activity. In vivo, neurons maintain a constant level of spontaneous activity which translates into synaptic input for each individual neuron. Synaptic input is known to affect the computational properties of neurons. Currently, in vitro investigation of synaptic integration relies on simulating synaptic activity through current injection at the soma or dendrite. This technique is limited to only one or two injection sites and can not address the still poorly understood dendritic integration of distributed synaptic inputs. In vivo, synaptic inputs constantly arrive at thousands of dendritic sites. In order to investigate synaptic integration at a more realistic level, it is necessary to control large numbers of synaptic inputs in space and time while measuring the response properties of the postsynaptic neuron. Here we propose to develop a new experimental technique, which will allow us to stimulate the dendritic trees of cortical pyramidal cells in vitro with precisely controlled spatio-temporal stimulus patterns. Our specific aims are: Aim 1) Adapt Digital Light Processing (DLP) technology (a matrix of several thousand individually controlled miniature mirrors) to be used as a dynamic photo stimulation (DPS) device. Stimulation occurs through photolytic uncaging of the excitatory neurotransmitter glutamate. UV light for glutamate uncaging will be controlled with DLP, allowing the artifact-free generation of 2-dimensional static or dynamic stimulus patterns. Aim 2) Use dynamic photo stimulation (DPS) to test the influence of synchronous "background" input on gain in neocortical neurons. We will use DPS to generate precisely defined spatio-temporal input patterns on the dendritic tree of cortical pyramidal cells while measuring neuronal responses. Acute slices are the method of choice for many studies related to human health, such as pharmacological studies of drug abuse or the evaluation of memory enhancing drugs. The improvements brought about by our new method will significantly expand the range of questions that can be addressed in acute slice preparations. The use of living slices of brain tissue to study the nervous system is the method of choice for many studies related to human health, such as pharmacological studies of drug abuse or the evaluation of memory enhancing drugs. The improvements brought about by the new method we propose to develop here will significantly expand the range of questions that can be addressed in living brain slice preparations. [unreadable] [unreadable] [unreadable]
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0.988 |
2008 — 2009 |
Foehring, Robert C (co-PI) [⬀] Heck, Detlef H. |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Role of Inhibition in Shaping Neocortical Activity: Normal Vs Fmr1 Knockout Mouse @ University of Tennessee Health Sci Ctr
DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited human mental retardation. Neuroanatomical studies of the brains of fragile X patients and of a mouse model of the disease (Fmr1 knock-out) showed a significantly altered morphology of neurons in the neocortex, cerebellum, as well as other parts of the brain. The key anatomical finding is that dendritic spines are abnormally thin and long, as well as increased in number. In healthy brains dendritic spines contain the postsynaptic terminals of excitatory synapses, suggesting that excitatory transmission may be altered in affected parts of FXS brains. In vitro studies have shown abnormal synaptic plasticity (increased LTD in hippocampus and decreased LTD in the neocortex). The cognitive, sensory, and behavioral deficits in human fragile X strongly implicate neocortical dysfunction. Based on the FXS-associated changes in spine morphology of cortical neurons, hypersensitivity to sensory input, and increased probability of seizures, the investigators hypothesize that cortical function in FXS patients is impaired due to increased excitability of the neocortical network. It is unclear whether the primary cause of these symptoms is increased excitability of pyramidal neurons, a reduced effectiveness of inhibitory interneurons, or a combination of these. Here the investigators propose to combine in vivo and in vitro electrophysiological experiments to determine how FXS changes the function of the cortical network in awake, behaving animals and how these network changes relate to alterations in synaptic transmission or excitability in different types of cortical neurons. This project will focus particularly on the effects of FXS on inhibition. The investigators will compare normal and Fmr1 knock-out mice using the whisker-barrel cortex as a model for neocortical function. The rodent whisker barrel cortex has two major advantages: 1) its normal function has been thoroughly investigated and documented, and 2) neurons in the barrel cortex express the typical anatomical abnormalities of fragile X brains. The proposed project has two aims: Specific Aim 1 will determine the effects of fragile X syndrome on (1) the function of the awake neocortical network, and (2) intracortical inhibition using the Frm1 knock-out mouse barrel cortex as a model. The investigators will use multiple electrode extracellular recording techniques to compare spontaneous and task-related neuronal activity in the barrel cortex of awake behaving wild-type and Fmr1 null mice. They will also determine the role of inhibition in shaping size and response properties of whisker barrel receptive fields. Specific Aim 2 will determine the effects of fragile X syndrome on excitability and synaptic transmission in fast spiking interneurons. The investigators in addition will address the potential cellular underpinning for network effects in Aim 1. They will also test whether defects in Frm1 null mice are restricted to neurons with spines or also include sparsely or aspiny interneurons. Immunocytochemistry will be used to test for FMRP expression in GABAergic interneurons and whole cell recordings for changes in intrinsic excitability, excitatory drive to interneurons, and the balance of excitation/inhibition on to layer V pyramidal neurons.
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0.988 |
2009 — 2013 |
Blaha, Charles (co-PI) [⬀] Goldowitz, Daniel (co-PI) [⬀] Heck, Detlef H. Mittleman, Guy [⬀] |
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. |
Cerebellar Modulation of Frontal Cortical Function
DESCRIPTION (provided by applicant): The developmental loss of cerebellar Purkinje cells that occurs in autism spectrum disorders has been associated with a heterogeneous pattern of cognitive deficits that cannot be explained by a unitary cognitive impairment. It is very unlikely that the simple loss of cerebellar Purkinje cells can directly account for these myriad cognitive deficits. Rather, it is likely that autism is, at its essence, a disconnection syndrome that results, at least in part, from a disruption of cerebellar modulation of the prefrontal cortex (PFC). We have exciting new data suggesting that the cerebellum modulates PFC dopamine levels. Here we propose to investigate the disconnection hypothesis that cerebellar pathology results in dopaminergic abnormalities in the prefrontal cortex (PFC) and underlies some of the core neuropsychiatric symptomatology of autism. In Aim 1 we will determine the pathway(s) whereby the cerebellum modulates dopamine release in the PFC and glutamate release in subnuclei comprising the cerebellum to PFC pathways and the neurochemical, electrophysiological, anatomical, and behavioral consequences of a disconnection between these two structures. Aim 1 will compare wildtype (control) and Lurcher mice that loose all Purkinje cells, to determine the consequences of complete loss of Purkinje cells on cerebellar-PFC communication. Aim 2 will investigate the behavioral and physiological consequences of partial loss of Purkinje cells - as typically found in autistic brains. Using Lurcher-wildtype chimeras with varying developmental loss in Purkinje cell numbers we will determine how neurochemical, electrophysiological, anatomical and behavioral indicators of PFC function depend on Purkinje cell number. Given the well documented reductions in cerebellar neuron number that are found in autism spectrum disorders, the neurochemical, electrophysiological, anatomical and behavioral analyses of chimeric mice presents a unique opportunity to model both the developmental and cerebellar aspects of these syndromes. PUBLIC HEALTH RELEVANCE Cerebellar and frontal cortical pathologies have been commonly reported in autism and other developmental disorders. The relationship between these two abnormalities is unknown. This proposal presents a framework for understanding how these seemingly disparate pathologies are related, and provides a unique opportunity for discovery of the neurochemical, electrophysiological and anatomical mechanisms whereby the cerebellum may modulate frontal cortical function, with particular focus on dopamine and Purkinje cell numbers. As the details of the functional interactions and adaptations within this neural circuitry become known, these neural substrates and associated receptor mechanisms should become new candidates for treatment of the cognitive deficits related to autism.
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0.964 |
2009 — 2012 |
Heck, Detlef 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. |
Coordination of Orofacial and Respiratory Movements @ University of Tennessee Health Sci Ctr
DESCRIPTION (provided by applicant): Ingestion of food and fluids are as integral to survival as is breathing oxygen, and it is not surprising that neural control substrates for both orofacial and respiratory movements are organized within pattern generating circuits in the brainstem. Constant coordination of these rhythmic movements is essential, and deficits in coordinating orofacial and respiratory movements are implicated in human health conditions such as sudden infant death syndrome (SIDS), swallowing dysfunction (dysphagia) and speech disorders (dysarthria). The cerebellum has long been implicated in the coordination of body movements and posture. Clinical evidence has also linked cerebellar dysfunction to SIDS, dysphagia and dysarthria but the neuronal mechanisms through which the cerebellum controls or coordinates respiratory and orofacial movements has yet to be determined. We have developed a new experimental paradigm that allows us to simultaneously measure orofacial (whisking and licking) and respiratory movements in awake behaving mice while recording neuronal activity in the cerebellum and brainstem. The highly stereotyped licking and whisking movements are in many respects ideal model behaviors for the study of cerebellar motor coordination. They are natural behaviors spontaneously performed in large numbers and easy to measure and quantify. Our preliminary experiments in awake behaving normal and ataxic mice show that respiration is well coordinated with whisking and licking in normal but not in ataxic mice. Here we propose to determine how licking, whisking and respiratory movements are coordinated in awake behaving mice, what role the cerebellum plays in this task and what neural circuitry is involved in this control. We hypothesize that the cerebellum coordinates the activities of brainstem pattern generators which generate respiratory and rhythmic orofacial movements. Three specific aims will test this hypothesis: Aim 1: Test the hypothesis that the precise temporal coordination between orofacial and respiratory movements is disrupted in mice with cerebellar ataxia. The coordination of orofacial and respiratory movements will be determined under different behavioral conditions in normal and ataxic mice and in normal mice during reversible inactivation of the deep cerebellar nuclei (DCN) through muscimol injections. Aim 2: Test the hypothesis that cerebellum and deep cerebellar nuclei neuronal activity is highly coordinated with orofacial and respiratory movements. We will use extracelluar recordings to map the neuronal representation of orofacial and respiratory movements in the cerebellum and deep cerebellar nuclei in normal and sensory deafferented mice under different behavioral conditions. Aim 3: Test the hypothesis that the cerebellum, via the fastigial nucleus of the DCN, coordinately controls rhythmic orofacial and respiratory movements via collateralized projections to multiple brainstem CPGs. Preliminary data show that Purkinje cells projecting to the fastigial nucleus (FN) represent multiple orofacial movements and that FN neurons project to multiple brain stem pattern generators. Brainstem tracer injections will be used to determine cerebellar to brainstem pattern generator projections. PUBLIC HEALTH RELEVANCE: Respiratory movements must be coordinated with other movements affecting airflow like speech, coughing, sneezing or swallowing, but how the nervous system achieves the important task of coordinating respiration with other orofacial movements is poorly understood. We have obtained preliminary data suggesting that the cerebellum is critically involved in this task, which could explain why cerebellar patients suffer from speech disorders (dysarthria) and difficulties in swallowing (dysphagia). The proposed studies will improve our general understanding of cerebellar function and particularly its involvement in the important task of coordinating respiration with other airflow-affecting movements.
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0.988 |
2011 — 2012 |
Heck, Detlef H. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Manipulation and Imaging of Synchronous Population Activity in the Neocortex @ University of Tennessee Health Sci Ctr
DESCRIPTION (provided by applicant): Understanding neuronal information processing and neuronal communication in massively interconnected networks like the neocortex is one of the great challenges of neuroscience. At the center of an ongoing debate about information processing in the neocortex is the question about the nature of the neuronal code used in the neocortical network, i.e. whether spike rates or precisely timed synchronous spike patterns carry and process information. There is substantial experimental evidence supporting the functional significance of synchronous spiking activity. Synchronized spikes have been shown to encode motor events, to represent visual, auditory and gustatory sensory information and to correlate with cognitive functions such as attention. However, the neurophysiological mechanisms underlying synchronized neocortical activity are only poorly understood. Two important open questions are: How sensitive are cortical neurons to synchronous synaptic inputs? When and how does synchronous activity propagate through the cortical network? Currently, most of our knowledge about the generation and propagation of synchronous neocortical activity is based on theoretical studies, as experimental approaches in biological networks have been technically challenging. Here we propose a powerful new optical approach to investigate the neurophysiological bases of synchronized activity in the neocortex. The approach uses our newly developed digital light processing (DLP)-based dynamic photo- stimulation system that allows the spatiotemporal control of in vitro cortical network activity using 786,000 independently controlled photo-stimulation sites. Dynamic photo-stimulation will be combined with voltage sensitive dye (VSD) imaging and intracellular electrophysiological recordings to monitor individual neuronal responses and the propagation of synchronized and un-synchronized population activity in the in vitro cortical network. The neurophysiological bases of human cognitive disorders such as schizophrenia or autism spectrum disorders are only poorly understood. A yet unexplored possibility is that the neocortical network's ability to generate, process and propagate synchronous population activity - which is believed to play a key role in higher cortical functions - is altered. Our approach provides new opportunities to investigate potential pathological changes in the processing of synchronous neuronal events in mouse models of human cognitive disorders. This might lead to valuable new insights into the neuropathology of cognitive disorders and inspire new treatment strategies.
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0.988 |
2015 — 2016 |
Heck, Detlef H. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Effects of Traumatic Brain Injury On Temporal Dynamics of Brain Activity and Learning @ University of Tennessee Health Sci Ctr
? DESCRIPTION (provided by applicant): Mild traumatic brain injury (TBI) can cause emotional and cognitive deficits that last for months to years after the traumatic event. These deficits prominently include depression and an inability to extinguish fearful memories (leading to fear perseveration), which are part of the Post Concussion Syndrome (PCS) as defined in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). Mild TBI typically results from a closed-head insult after a primary blast shock wave, a blow to the head, or head acceleration - deceleration during a collision. It is an extremely frequent occurrence during military combat, sports, recreational activities, and vehicular accidents and thus constitutes a significant public mental health problem. The major brain pathology observed after mild TBI is diffuse axonal injury, although persistent neuronal dysfunction is suspected as well. The precise brain regions whose connectivity and function are disrupted by mild TBI so as to cause neuropsychiatric deficits have been uncertain. Based on our initial findings, we propose to use a mouse model of mild TBI to study the role of electrophysiological abnormalities in medial prefrontal cortex (mPFC) in the genesis of fear perseveration and depression, two of the more disabling neuropsychiatric sequela of mild TBI, for which there is currently no treatment. We will also confirm that a novel drug that we have shown to reduce depression and fear after mild TBI in mice, does so by normalizing mPFC coherence. Our proposed studies are based on our preliminary findings using multi-site recordings of neuronal activity in mice with mild TBI, caused by a precisely controlled overpressure air blast restricted to the cranium overlying the left forebrain. Our results suggest that abnormal phase coherence of neuronal firing in the medial prefrontal cortex (mPFC) is persistently present in mice that show enduring depression and an inability to extinguish fear memories up to one year after they experienced mild TBI. By contrast, mice that had experienced a subconcussive air blast or a sham air blast showed normal coherence of neuronal firing in mPFC and no depression or perseverative fear afterwards. Furthermore, treating mice with the novel drug (the cannabinoid type-2 receptor inverse agonist SMM-189) not only ameliorated fear and depression at 1 month after mTBI, it also restored coherence in the mPFC to normal values. Confirmation of our preliminary findings is thus likely to advance our understanding of the neuronal mechanisms behind persistent depression and fear after mild TBI, and may provide an electrophysiological signature that can be used to identify those humans whose persistent depression and fear is likely to arise from mTBI. We therefore propose to test the hypothesis that coherence of neuronal oscillations in mPFC is tightly associated with and thus causal to the persistent depression and fear after mild TBI. We also propose to test the hypothesis that SMM-189 rescues mTBI related fear and depression deficits in mice by restoring normal neuronal coherence in the mPFC, and that further investigation of SMM-189 may thus lead to a possible pharmacological treatment for mTBI.
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0.988 |
2018 — 2021 |
Heck, Detlef 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. |
Neuronal Mechanisms of Cerebellar Cognitive Function @ University of Tennessee Health Sci Ctr
Understanding human cognition is one of the cornerstones of the CDC's Healthy Brain Initiative (see https://www.cdc.gov/aging/healthybrain/). The cerebellum was long perceived as an exclusively motor-related structure, but it is now also increasingly recognized for its involvement in cognition, in both humans and animals. In recent years clinical and animal studies have shown that cerebellar activation is correlated with cognitive functions such as spatial working memory, and that cerebellar neuropathology can cause deficits in those functions. Cerebellar neuropathology is also known to be correlated with mental illnesses like autism, schizophrenia, dementia and Alzheimer's disease. Thus, understanding cognitive function and mental illnesses requires understanding the role of the cerebellum in cognition. However, existing evidence is purely correlational and a neuronal mechanism for cerebellar cognitive involvement has yet to be identified. The main barrier to investigating cerebellar cognitive function is that obtaining causal evidence and exploring neuronal mechanisms requires experiments involving controlled manipulations of cerebellar function while simultaneously observing cognitive behavior and neuronal activity. The availability of neuro- and optogenetic tools, awake-behaving electrophysiological techniques and quantitative tests for cognitive behaviors in mice now allow this barrier to be surmounted. We propose studies designed to answer fundamental questions about the role of the cerebellum in cognition using mice as our model organism and spatial working memory (SWM) as a quantifiable cognitive function known to involve the cerebellum in both humans and rodents. Our central hypothesis is that the cerebellum controls SWM decision-making by controlling decision-related coherence of neuronal oscillations between the medial prefrontal cortex (mPFC) and the hippocampus (HC). The mPFC and HC each are reciprocally connected with the cerebellum and play key roles in SWM. The decision-making process in SWM tasks is characterized by a temporary increase in coherence between the mPFC and HC. This decision-related coherence is believed to be a requirement for normal SWM performance. We propose to use a new mouse model of cerebellar dysfunction created by co-PI Sillitoe and electrophysiological recordings in freely moving mice to test the hypothesis that loss of cerebellar function causes severe SWM deficits and loss of SWM decision-related coherence increase. We propose to employ optogenetic techniques to manipulate cerebellar activity during SWM behavior to provide causal evidence for cerebellar involvement in SWM and to map cerebellar cortical areas involved in controlling SWM. Our preliminary data strongly support our hypotheses. Our work will broadly impact our understanding of the role of the cerebellum in cognitive brain function and the mechanisms linking cerebellar neuropathology to mental illness, which makes this project directly relevant to the mission of the NIH.
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0.988 |
2019 |
Heck, Detlef 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. |
Cerebrocerebellar Interaction Deficits in Alzheimer's Disease @ University of Tennessee Health Sci Ctr
Understanding human cognition is one of the cornerstones of the CDC's Healthy Brain Initiative (see https://www.cdc.gov/aging/healthybrain/). The cerebellum was long perceived as an exclusively motor-related structure, but it is now also increasingly recognized for its involvement in cognition, in both humans and animals. In recent years clinical and animal studies have shown that cerebellar activation is correlated with cognitive functions such as spatial working memory, and that cerebellar neuropathology can cause deficits in those functions. Cerebellar neuropathology is also known to be correlated with mental illnesses like autism, schizophrenia, dementia and Alzheimer's disease (AD). Thus, understanding cognitive function and mental illnesses like AD requires understanding the role of the cerebellum in cognition and cognitive decline. Existing evidence is purely correlational and thus far, no neuronal mechanism has been identified. The main barrier to investigating cerebellar cognitive function is that obtaining causal evidence and exploring neuronal mechanisms requires experiments involving controlled manipulations of cerebellar function while simultaneously observing cognitive behavior and neuronal activity. The availability of neuro- and optogenetic tools, awake-behaving electrophysiological techniques and quantitative tests for cognitive behaviors in mice now allow this barrier to be surmounted. We propose studies designed to answer fundamental questions about the role of the cerebellum in cognition and cognitive decline in AD using spatial working memory (SWM) as a quantifiable cognitive function known to involve the cerebellum in both humans and rodents. Our central hypothesis is that the cerebellum controls SWM decision-making by controlling decision-related coherence of neuronal oscillations between the medial prefrontal cortex (mPFC) and the hippocampus (HC). The mPFC and HC are both connected with the cerebellum and play key roles in SWM. Decision-making in SWM is characterized by an increase in mPFC-HC coherence, which is believed to be a requirement for normal SWM performance and which we hypothesize requires the cerebellum. For this AD-specific administrative supplement we propose to investigate the role of the cerebellum in cognitive decline in AD using use two different mouse models AD: the APP KI mice, which replicate A? plaque accumulation in human AD, and the PS19 mice, which replicate tau tangle accumulation in human AD. We will conduct electrophysiological recordings in freely moving mice to test the hypothesis that AD results in deficits in cerebellar control of mPFC-HC coherence and SWM. We propose to use optogenetic manipulation of cerebellar activity to provide causal evidence for our hypothesis that AD results in reduced cerebellar control of mPFC-HC coherence deficits in SWM. Our preliminary data support our hypotheses. Our work will significantly impact our understanding of the role of the cerebellum in cognitive decline in AD, which makes this project directly relevant to the purpose of the AD-focused Administrative Supplement NOT-AG-18-039.
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0.988 |