2007 — 2010 |
Ahmed, Omar Jamil |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
The Role of Inhibitory Mechanisms On Governing the Hippocampal Temporal Code
[unreadable] DESCRIPTION (provided by applicant): The hippocampus has a well established role in learning and memory (Scoville & Milner, 1957; Squire, 1992), and hippocampal damage is primarily responsible for the memory impairments resulting from a variety of neurological conditions such as Alzheimer's disease, epilepsy and stroke. In vivo electrophysiological studies of the hippocampus have revealed some salient activity patterns. Specifically, hippocampal cells in both rodents and humans fire in a spatially selective manner (O'Keefe and Dostrovsky, 1971; O'Keefe and Recce, 1993; Ekstrom et al., 2003, 2005). Both the firing-rate (rate code) and spike-timing (temporal code) contain information about the spatial environment. However, the cellular and circuit mechanisms that give rise to the hippocampal rate and temporal codes are still not well understood, and little is known about how inhibition shapes these hippocampal activity patterns. I will combine in vivo and in vitro experiments with computational modeling to investigate the inhibitory mechanisms governing the hippocampal temporal code. Using such an understanding, we can precisely pinpoint what properties of the circuit are crucial for hippocampal function. This can point us towards novel targets for treating clinical ailments resulting from hippocampal damage. Relevance: The human hippocampus is important for learning and memory but it is prone to damage: strokes, dementias (including Alzheimer's disease), epilepsies and hypoxia can all lead to hippocampal damage, and subsequent learning and memory difficulties. By understanding the neural code of the hippocampus we can precisely pinpoint which of its cells and circuits are crucial for learning and memory. This can point us towards novel targets for treating problems resulting from hippocampal damage. [unreadable] [unreadable] [unreadable]
|
0.931 |
2013 |
Ahmed, Omar Jamil |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Inhibitory Single Neuron Control of Human Epilepsy @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): Epilepsy is an often debilitating neurological condition affecting 3 million Americans and more than 50 million people across the globe. Despite several decades of excellent clinical, genetic and basic research and the existence of dozens of animal models and hypotheses, the mechanisms underlying human focal epilepsy are still not understood. To achieve the no seizures, no side effects goal of epilepsy research, we need to first answer a set of fundamental questions: how do focal seizures start, how do they spread, and how do they terminate? In particular, what roles do different subsets of neurons - inhibitory vs excitatory - play in the progression of human seizures? Intracranial electrocorticogram (ECoG) recordings in patients with intractable epilepsy are used to localize the brain region where seizures originate. ECoG signals represent the summed activity of thousands of neurons, and have revealed many important macroscopic features of seizures. However, many of the mechanistic predictions arising from animal models of epilepsy are at the level of individual neurons, and cannot be tested using ECoG alone. Here, specially designed recording techniques and devices are used to safely record the simultaneous activity of hundreds of individual neurons during seizures directly in patients with pharmacoresistant focal epilepsy. It i then possible to selectively identify human inhibitory neurons and ask how they control seizures. Many animal and slice studies state that decreased inhibition leads to seizures. However, many others state that increased inhibition is necessary to synchronize activity before a seizure can occur. Direct recordings of these inhibitory interneurons from humans present a unique opportunity to resolve this debate. By carefully identifying human inhibitory interneurons it is possible to characterize how they behave during all phases of human seizures. The activity of these human inhibitory interneurons can then be compared to that of different kinds of excitatory cells. The activity of inihibitory neurons can then also be manipulated optogenetically in mouse models of epilepsy to confirm that the human observations linking inhibitory neuron activity and seizure intensity are causal, and not just correlative. This can point the field towards novel pharmacological, surgical and predictive therapies for epilepsy that specifically target particular neuronal subtypes.
|
0.904 |
2021 |
Ahmed, Omar Jamil |
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.) |
The Retrosplenial Gate Hypothesis For Anterior Thalamic Stimulation in Temporal Lobe Epilepsy (Diversity Supplement) @ University of Michigan At Ann Arbor
PROJECT SUMMARY / ABSTRACT Deep brain stimulation of the anterior thalamic nuclei can reduce the number of seizures in patients with intractable temporal lobe epilepsy, but rarely leads to complete remission. The mechanisms of action underlying these therapeutic benefits remain unknown. We have identified a specific pathway by which anterior thalamic stimulation may induce an inhibitory firewall in a brain region called the retrosplenial cortex, potentially preventing the spread of seizures. The hippocampal formation sends dense outputs to the superficial layers of the retrosplenial granular cortex (RSG) via the subiculum. Anterior thalamic axons converge onto exactly the same RSG circuit. The retrosplenial cortex then projects to dozens of neocortical regions, including the secondary motor cortex, and is thus a critical gateway via which seizures can spread from the hippocampus to the neocortex, leading to secondarily generalized motor seizures. Despite this important connectivity, the cells and circuits of the retrosplenial cortex are massively understudied in epilepsy. We have discovered a new cell type in the RSG and found that this brain region is dominated by local inhibition. Our recordings show that anterior thalamic inputs to the retrosplenial cortex strongly recruit this inhibitory circuitry and identify a unique pathway for the thalamic recruitment of fast-spiking inhibitory neurons in RSG, via both layer 1 and layer 3. This pronounced inhibition can silence the excitatory neurons of the RSG, potentially preventing the propagation of seizure activity to the rest of the neocortex. Our retrosplenial gate hypothesis posits that the inhibition-dominated retrosplenial circuitry recruited by anterior thalamic stimulation can prevent the spread of temporal lobe seizures to the neocortex and partially explain the therapeutic mechanisms underlying anterior thalamic DBS. In Aim 1 we will characterize simultaneous neuronal dynamics in the hippocampus, retrosplenial cortex, secondary motor cortex and anterior thalamus in a rodent model of chronic temporal lobe epilepsy. In Aim 2, we will causally test the retrosplenial gate hypothesis by attempting to prevent the spread of temporal lobe seizures to the neocortex using the closed- loop optogenetic stimulation of anterior thalamic projections specifically to the retosplenial cortex. Therapeutic benefits will be compared to optogenetic stimulation of anterior thalamic projections to alternative cortical regions. The successful completion of these aims has the potential to identify a novel, precise and rational therapeutic pathway for the treatment of temporal lobe epilepsy.
|
1 |
2021 |
Ahmed, Omar Jamil |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Udall Catalyst Research Project: Retrosplenial Cholinergic and Attentional-Motor Integration Dysfunction @ University of Michigan At Ann Arbor
CATALYST RESEARCH PROJECT: SUMMARY/ABSTRACT Many patients with Parkinson?s disease (PD) suffer from spatial disorientation ? inability to link external landmark cues to internal estimates of self-orientation. These deficits are not improved by dopamine replacement therapy (DRT). The same spatial disorientation features are found in patients with specific lesions, due to a stroke or hemorrhage, of the retrosplenial cortex (RSC), a brain region critical for encoding the combination of allocentric and egocentric navigational information. Attentional and emotional processing impairments in PD patients are accompanied by altered BOLD responses in the retrosplenial cortex. The retrosplenial cortex is densely interconnected with the secondary motor cortex, hippocampus, visual cortex, cingulate cortex and anterior thalamus (containing head orientation cells), and is therefore part of the Attentional-Motor Interface (AMI) and ideally positioned to help transform attentional and spatial information into planned actions. Furthermore, multiple basal forebrain structures send cholinergic projections to the RSC. There are pronounced increases in acetylcholine (ACh) release in the retrosplenial cortex during attentive spatial navigation. Cholinergic deficits, such as those seen in PD, are likely to severely impair the spatial orientation functions of the retrosplenial cortex. Little is known about 1) how cholinergic inputs influence the synapses, cells and circuits of the retrosplenial circuits, and 2) the impact of cholinergic dysfunction on retrosplenial-dependent spatial orientation and navigation. Our central hypothesis is that dysfunctional cholinergic systems projecting to the retrosplenial cortex will manifest in altered navigational encoding by retrosplenial circuits and spatially disoriented behaviors. In Aim 1, we will decipher the mechanisms of cholinergic control of retrosplenial cells and synapses, with preliminary data suggesting both cell-type- and synapse-specific cholinergic controls. In Aim 2, we will investigate how the loss of cholinergic inputs impairs retrosplenial encoding of space and how it impacts orientation-guided movement. The successful completion of these Aims will elucidate the contributions of the retrosplenial orientation coding circuit to the Attentional-Motor Interface, and lay the groundwork for understanding how altered perception of spatial orientation in Parkinson?s disease can directly impact motor control.
|
1 |