Andrew P. Maurer - US grants

DESCRIPTION (provided by applicant): Under static conditions, cells in the primate medial temporal lobe have been shown to selectively fire to objects or the location of objects in front of the monkey (Rolls et al., 1989;Riches et al., 1991). After examining conditions of movement, however, hippocampal activity was found to be affected by specific visual stimuli in an environment, places within an environment, task-related cues, or a combination of these (Ono et al., 1991;1993). Additionally, some neurons within the primate hippocampus have been observed to fire in relation to the specific direction of gaze towards a location in space ("spatial view";O'Mara &Rolls, 1995). Wirth and colleagues (2003) observed that during the acquisition of new place-stimuli associations, a portion of neurons altered their activity based on the behavioral performance, suggesting a mechanism by which memories could be stored long-term. Although the role of the hippocampus in memory encoding and consolidation is virtually undisputed, it is not known whether single cells in the primate hippocampus are preferentially driven by sensory stimuli, or exhibit entirely different correlates during unrestrained movement. It has not been possible to test this hypothesis directly until recently due to technological limitations. Developments by our long-time collaborators at Neuralynx, Inc. have provided the means to investigate this issue through the use of telemetric recordings. Moreover, the system has the battery capacity to record for up to 6 hours, enabling data to be collected during behavioral epochs as well as during periods of sleep and quiet-wakefulness. Although activity pattern reactivation during these 'off-line'periods has been documented in several cortical regions of the primate (Hoffman and McNaughton, 2002), direct recordings within the hippocampus have not yet been performed. Because ripple/sharp-wave events have recently been found to occur in histologically-verified hippocampal regions of the nonhuman primate (Skaggs et al., 2007), it is reasonable to hypothesize that neural activity patterns observed during behavior will be reactivated during these periods of sharp waves (Kudrimoti et al., 1999). The goals of this proposal can be summarized in the following two aims: 1) to determine whether active versus passive movement affects the firing correlates of hippocampal neurons when the animal is shuttling for food reward compared to the condition where the animal is passively moved to between reward locations within the same environment, and 2) to examine whether neural ensembles active during behavior are reactivated during sharp-wave/ripple epochs. These studies will provide definitive classifications of hippocampal single unit activity and EEG in the primate during naturalistic behaviors and will provide significant insights into the correlates of hippocampal activity patterns during sleep and waking states. PUBLIC HEALTH RELEVANCE: The outcome of the proposed project will have a significant impact on our understanding of the neural basis of episodic memory and how the hippocampus, a prominent structure in the brain, supports this cognitive process. A more comprehensive understanding of hippocampal function is a prerequisite for successful development of therapeutic or preventative treatments for neurological disorders that selectively impact this structure, such as Alzheimer's disease. Moreover, these data will provide new approaches to studying, and ultimately ameliorating, memory disorders arising from other sources such as aging, stress, drug abuse, and brain trauma.

DESCRIPTION (provided by applicant): Under static conditions, cells in the primate medial temporal lobe have been shown to selectively fire to objects or the location of objects in front of the monkey (Rolls et al., 1989; Riches et al., 1991). After examining conditions of movement, however, hippocampal activity was found to be affected by specific visual stimuli in an environment, places within an environment, task-related cues, or a combination of these (Ono et al., 1991; 1993). Additionally, some neurons within the primate hippocampus have been observed to fire in relation to the specific direction of gaze towards a location in space (spatial view; O'Mara & Rolls, 1995). Wirth and colleagues (2003) observed that during the acquisition of new place-stimuli associations, a portion of neurons altered their activity based on the behavioral performance, suggesting a mechanism by which memories could be stored long-term. Although the role of the hippocampus in memory encoding and consolidation is virtually undisputed, it is not known whether single cells in the primate hippocampus are preferentially driven by sensory stimuli, or exhibit entirely different correlates during unrestrained movement. It has not been possible to test this hypothesis directly until recently due to technological limitations. Developments by our long-time collaborators at Neuralynx, Inc. have provided the means to investigate this issue through the use of telemetric recordings. Moreover, the system has the battery capacity to record for up to 6 hours, enabling data to be collected during behavioral epochs as well as during periods of sleep and quiet-wakefulness. Although activity pattern reactivation during these 'off-line' periods has been documented in several cortical regions of the primate (Hoffman and McNaughton, 2002), direct recordings within the hippocampus have not yet been performed. Because ripple/sharp-wave events have recently been found to occur in histologically-verified hippocampal regions of the nonhuman primate (Skaggs et al., 2007), it is reasonable to hypothesize that neural activity patterns observed during behavior will be reactivated during these periods of sharp waves (Kudrimoti et al., 1999). The goals of this proposal can be summarized in the following two aims: 1) to determine whether active versus passive movement affects the firing correlates of hippocampal neurons when the animal is shuttling for food reward compared to the condition where the animal is passively moved to between reward locations within the same environment, and 2) to examine whether neural ensembles active during behavior are reactivated during sharp-wave/ripple epochs. These studies will provide definitive classifications of hippocampal single unit activity and EEG in the primate during naturalistic behaviors and will provide significant insights into the correlates of hippocampal activity patterns during sleep and waking states.

? DESCRIPTION (provided by applicant):: Cannabis is the most widely-used illicit drug in the U.S., and over 1 million people are treated for cannabis dependence annually. Given the potential for dependence as well as deleterious effects of chronic use, there is an urgent need to better understand the mechanisms supporting cannabis use, in order to develop therapies to reduce such use. There are several animal models in which reliable intravenous self-administration of cannabinoids such as ?9THC (THC) has been demonstrated. Most human use, however, occurs through inhalation of cannabis smoke, which contains numerous cannabinoids aside from THC, some of which is psychoactive and may interact with THC to alter its reinforcing effects. Hence, an animal model that employs cannabis smoke self-administration would more closely mimic the conditions of actual human use, and would open new directions of research on cannabis use and abuse. The long-term goal of this research program is to use rodent models to investigate the reinforcing effects of smoked cannabis, with the ultimate goal of developing therapies for reducing cannabis use/abuse. As the first step toward this goal, the objective of this CEBRA R21 project is to develop and validate a system by which rats can self-administer cannabis smoke. To our knowledge, there are no reports of self-administration of smoked drugs of abuse in rodents; however, there have been several demonstrations in primates of reliable self-administration of smoked drugs of abuse, including cocaine and heroin. In addition, we have preliminary data showing development of dependence following passive cannabis smoke administration in rats, demonstrating the efficacy of cannabis smoke as a drug delivery vehicle in this species. On the basis of these published and preliminary data, our central hypothesis is that rats will self-administer cannabis smoke, and that smoke self-administration behavior will be similar to that reported for intravenous cannabinoids and other drugs of abuse. We have designed an apparatus that will allow precisely-calibrated, response-contingent delivery of cannabis smoke using experimental designs similar to those employed with other drugs of abuse. We will use this apparatus to determine whether rats will reliably show operant responding for cannabis smoke delivery, and whether this responding is sensitive to smoke THC content and CB1 receptor activation, as well as to cues predictive of smoke delivery. We have also developed multiple strategies to increase the likelihood of obtaining self-administration behavior. Successful development of a rodent cannabis smoke self-administration model will lay the groundwork for a larger research program on neurobehavioral mechanisms of cannabis smoking. In addition, this model could be adapted for use with other smoked drugs of abuse (e.g., tobacco).

? DESCRIPTION (provided by applicant): By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, even in the absence of significant neuropathology, a large proportion of elderly people will experience memory decline that will interfere with their instrumental activities of daiy living. The hippocampus is critical for memory and is subject to dysfunction during aging. Importantly, the dentate gyrus subregion of the hippocampus is one of only two brain regions in which new neurons are born and integrated into existing neural circuits; a process referred to as neurogenesis. Neurogenesis declines with age, but it is not known how this contributes to cognitive impairments. Although neurogenesis could have vital functions for normal memory, there is a fundamental gap in our knowledge of how this process impacts neuronal networks both within the dentate gyrus as well as in the brain regions that receive direct input from this structure. Moreover, to date, there is not a single report of the in vivo physiological characteristics of dentate gyrus neurons in aged animals. The long-term goal of the proposed research plan is to pinpoint disruptions in the neural circuits of old animals that can then be restored through therapeutic or behavioral interventions to reduce cognitive impairments in the elderly. The objective in this particular application is to determine how neurogenesis levels impact hippocampal-dependent behaviors and the dynamics of neural networks within the dentate gyrus and its primary efferent target, CA3. The central hypothesis is that the integration of newborn neurons is critical for dynamic hippocampal representations needed to support complex behaviors. The rationale for the proposed research is that understanding the functional importance of neurogenesis and how dentate gyrus and CA3 cellular activity dynamics are impacted by lower numbers of newborn neurons could direct clinical treatments for cognitive deficits associated with aging that are going to become more prevalent as the number of elderly people in the U.S. continues to grow. The hypothesis will be tested with 2 specific aims: 1) identify how age- related neurogenesis decline impact dentate gyrus circuit dynamics, and 2) quantify the impact of age- associated functional changes in the dentate gyrus on CA3. These aims will be achieved through the use of high-channel count neural recordings that allow single-cell activity to be monitored from up to hundreds of neurons across multiple brain regions simultaneously in behaving rats. This is an innovative approach that optimizes power for detecting neural-behavioral relationships.

Title: Testing and forecasting hippocampal theta wave propagation in learning and memory Abstract: Psychiatric disease states are associated with profound deficits in cognition that can severely compromise one's ability to live independently. In order to understand and effectively treat mental health disorders, it is necessary to determine how the information that supports adaptive behaviors is relayed across large networks of neurons. Brain rhythms, such as local field potential oscillations, have been hypothesized to organize neural circuit processing on multiple timescales in order to coordinate thought and action. Moreover, abnormalities in brain rhythms have been observed in humans afflicted with schizophrenia, autism, bipolar disorder, and a wide array of other neurological diseases. Among the neural oscillations affected by psychiatric diseases is the hippocampal theta rhythm, which is critical for learning and memory and is disrupted in schizophrenia and anxiety disorders. Importantly, the theta oscillation has been found to propagate along the hippocampal dorsoventral axis. Although the propagating theta wave has never been explicitly examined in the context of a cognitive task, this traveling brain rhythm could serve the fundamental purpose of integrating information across the hippocampus in support of learning and memory. The long-term goal of this research is to determine how neurons act in concert to guide behavior and to develop novel therapeutic strategies for normalizing brain rhythms in disease. The primary objective of the current proposal, which is the first step toward attaining our long-term goal, is to determine the behavioral and cellular mechanisms that modulate wave propagation, and to forecast oscillatory activity across brain regions. We will attain this by testing the central hypothesis that the propagation of the theta oscillation, coordinated via septal and entorhinal influences, can be described as a weakly nonlinear wave, altering its dynamics as a function of learning and memory with the following specific aims: 1) Determine the influence of cognition and septal input on hippocampal theta wave propagation, 2) Determine the influence of medial entorhinal input on hippocampal theta wave propagation, and 3) Develop a nonlinear algorithm to forecast theta wave propagation. The rationale is that this approach will uncover fundamental principles of wave propagation that will enable new insight into neuronal coordination in the normal brain and mechanisms of dysfunction in neuropsychiatric illness. This proposal is innovative because we will integrate cross-disciplinary theoretical and empirical approaches to develop an integrated understanding of large-scale neuronal dynamics. The significance of this contribution is an unprecedented understanding of activity propagation in the hippocampus during learning and memory that will provide insights into the temporal coordination of information, developing the critical foundation for understanding how cognition is disrupted in psychiatric disease.

Over the past century, we have witnessed remarkable increases in the average life span. Unfortunately, increased longevity is not matched by the typical health span, and most elderly individuals will experience memory decline that interferes with their quality of life and ability to maintain independence. The hippocampus is critical for memory and is one of the brain regions vulnerable in advanced age and Alzheimer?s disease. Because onset of Alzheimer?s disease is generally after the age of 65, the biological foundations of this neurodegenerative disorder are compounded by normal age-associated declines that we do not fully understand. In fact, alterations in the hippocampal circuit with old age could either reflect synaptic senescence or adaptive plasticity compensating to normalize output. Unfortunately, we have insufficient information to distinguish between these two competing hypotheses that would lend to distinct treatment strategies. The long-term goal of the proposed research is to determine the alterations in hippocampal subregion interactions that underlie cognitive dysfunction. The primary objective of the current proposal is to determine how altered communication within the hippocampal circuit in old age produces memory deficits. Linking neurobiology directly to behavior, will allow us to determine if synaptic alterations are adaptive or the underlying cause of dysfunction. We will attain this by testing the central hypothesis that altered communication between CA3 and CA1 results from a deafferentation of the hippocampus from the entorhinal cortical (ERC), which leads to CA3 hyperexcitability. Old animals that maintain high performance, adapt to the loss of ERC input by weakening the CA3 to CA1 Schaffer collateral synapse to impede the propagation of aberrant activity. In contrast, aged animals will impairments show enhanced CA3-CA1 coupling. This hypothesis will be tested with the following specific aims: 1) Determine how CA3-CA1 neuron spike timing contributes to memory decline in old animals, 2) Determine the role of perforant path loss in intrinsic hippocampal dysfunction, and 3) Determine how changes in medial temporal lobe synchrony in old age map onto memory dysfunction. The rationale is that by elucidating how aging and disease influence systems-level dynamics, we will be better positioned to develop interventions that broadly improve cognition. The proposed research is innovative, in our opinion, as neurophysiological techniques will be integrated with measures of behavior in young and aged rats in order to probe how local dysfunction manifests as network impairments or incites compensatory processes. The significance of the successful completion of this work will be to determine how distinct types of cellular dysfunction alter global circuit properties in order to identify and exploit network mechanisms to ultimately improve cognition.

TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development FOA type: PAR-19-289: Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder, schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2) Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the therapeutic development pipeline for treating mental illness.