John P. McGann - US grants

DESCRIPTION (Adapted from applicant?s abstract): Behavioral studies have implicated the D2 dopamine receptor in the timing of seconds-range intervals. Separate behavioral investigations have demonstrated that the perirhinal cortex (PR) is important in tasks that require temporal information processing of similar intervals. Recent cellular studies of PR further motivate the idea that PR is involved in temporal aspects of information processing and these ideas have been incorporated into circuit-level computational models. One relevant fact about PR is the large proportion of late-spiking (LS) neurons. These cells delay the onset of their spiking for several seconds relative to the onset of a current clamp step or a train of synaptic inputs. This delay feature is an essential part of the computational model of timing in PR. LS neurons are particularly common in the cortical layers that contain substantial numbers of D2 dopamine receptors. The preceding, taken together, is part of the basis of my interest in exploring the roll of dopamine (DA) physiology in PR, particularly with regard to LS neurons. The overarching idea is that DA alters temporal aspects of information processing in PR by modifying the delay properties of LS neurons through the D2 receptor. The specific hypotheses that I plan to test evaluates the proposition that dopamine can modulate a slowly-inactivating potassium current that is responsible for late-spiking. The results will furnish a conductance mechanism for LS in PR and hopefully elucidate the mechanism by which DA alters this conductance and thereby modulates firing latency in LS neurons. The results should furnish insight into the role of D2 receptors in PR, and as explained inside, are highly relevant to public health.

[unreadable] DESCRIPTION (provided by applicant): Experiments using early sensory deprivation to alter the development of the visual and auditory systems have produced seminal work in those fields. Olfactory deprivation in the neonatal rodent has been shown to evoke dramatic anatomical and neurochemical changes in the olfactory system during development, but little is known about the corresponding functional changes during deprivation and recovery. Dr. Wachowiak and collaborators have demonstrated a transgenic mouse model in which the synaptic terminals of olfactory receptor neurons (ORNs) fluoresce when they release transmitter, permitting the in vivo imaging of ORN synaptic output in the olfactory bulb during odorant presentation. The use of these mice, therefore, provides novel opportunities to investigate the effects of sensory deprivation on the functional development of the olfactory system. The work proposed here will use these mice to study the effects of olfactory deprivation during development on synaptic transmitter release from ORNs and its presynaptic modulation by olfactory bulb circuitry, as well as the recovery from deprivation following the reopening of the naris. This research will provide new insights into the activity-dependent development and regulation of the olfactory system. [unreadable] [unreadable]

The olfactory system provides a uniquely powerful environment in which to explore sensory plasticity in mammals, because the earliest central processing in the olfactory system takes place in the glomeruli of the olfactory bulb, a structure that is physically and optically accessible in vivo in animal models, and because recent advances in molecular genetic technology have produced excellent experimental tools for studies in this area. Using a combination of molecular genetic tools and in vivo optical imaging techniques, I have recently shown that the olfactory system exhibits rapid feedback presynaptic inhibition of transmitter release from the olfactory nerve. I hypothesize that the rapid plasticity of this circuit provides adaptive gain control for the primary sensory input from the nose, and thus plays a major role in the encoding of odorant concentration and the perception of odor intensity. Moreover, preliminary data suggest that this inhibitory circuitry may change over time to accommodate changes in the olfactory environment. The first aim of these experiments is to test the hypothesis that this presynaptic modulation of primary sensory input to the olfactory bulb contributes to the encoding of odor concentration. The second aim of these experiments is to use optical imaging techniques to test the hypothesis that changes in sensory environment induces plasticity in the representation of odors at the input to the olfactory bulb. The final aim of these experiments is to use behavioral assays to test how this plasticity affects the perception of odor quality and intensity.

DESCRIPTION (provided by applicant): A growing body of scientific literature indicates that sensory processing in the nervous system incorporates not just bottom-up analysis of sensory information that originates from the sensory organs but also top-down expectations about the organization of the sensory world that derive from previous sensory experience. In the olfactory system the first convergence of bottom-up and top-down projections occurs in the glomeruli of the olfactory bulb, where optical imaging techniques now permit the visualization of presynaptic calcium signaling and neurotransmitter release from olfactory receptor neurons (the very first neurons in the olfactory system) in awake mice that are smelling odors and learning about their environment. The olfactory system is thus a uniquely powerful model system to study the synthesis of top-down and bottom-up information. Remarkably, in preliminary experiments we have found that this primary sensory input is strongly modulated by the mouse's expectations about olfactory stimuli, as established by prior sensory experience during the imaging session. For instance, if an odor is always presented after a warning tone cue, the unexpected presentation of that odor without the tone evokes much less presynaptic calcium influx and less neurotransmitter release from the olfactory nerve than when the odor follows the cue. This effect appears to occur via a GABAB receptor-mediated presynaptic inhibition of neurotransmitter release from these synapses. Because the output of the receptor neurons themselves is modulated by expectations, these data suggest that there is actually no purely bottom-up information in the olfactory system at all. This has profound implications for our understanding of neural representations of olfactory stimuli and will inform our understanding of other, less experimentally tractable sensory systems. This proposal confirms and extends these findings by testing the nature of the expectations (e.g. is the expectation odor-specific?), their time course (e.g. are expectation effects anticipatory?), and their neural mechanisms (e.g. are descending projections to the olfactory bulb necessary during the establishment of the expectation or only for detecting unexpected outcomes?). Further experimentation is designed to reveal the perceptual consequences of these neural changes (e.g. do expected odors smell stronger than unexpected odors?) and whether the difference in neurotransmitter release from receptor neurons is necessary for these perceptual effects to occur. Importantly, this work will be designed and analyzed in the context of information theory, a formal theory that allows the quantification of how expected or surprising a given stimulus is and thus provides testable quantitative predictions for assessing the neurophysiological and psychophysical consequences of expectation. These results should provide an essential step in understanding how cognition can play a role in perception as early as the first neurons in a sensory system.

DESCRIPTION (provided by applicant): Fear learning permits an animal to respond adaptively to threatening circumstances (Bolles 1970). However, dysregulation of the brain's systems for fear learning can lead to debilitating anxiety disorders (Rosen and Schulkin 1998), including post-traumatic stress disorder (PTSD). In preliminary experiments in a mouse model of olfactory fear learning, longitudinal optical imaging experiments revealed large, associative, stimulus- specific increases in neurotransmitter release from olfactory sensory neurons (OSNs) when they are stimulated by fear-associated odors (CS+) in vivo. This neural response to the CS+ is enhanced after conditioning both compared to responses to neutral odors and compared to its own pre-conditioning baseline, thus showing that fear conditioning selectively changes the neural representation of the CS+ at the input to the brain. After fear conditioning, these primary sensory responses to footshock-predictive odors were actually larger than could be evoked by any concentration of that odor under control circumstances, perhaps serving as a warning signal to enhance reaction to the CS+ or to draw attention to it. This result suggests that changes in sensory processing of threat-related stimuli could play a role in anxiety disorders, which include a ubiquitous attentional bias toward dangerous or unpleasant stimuli. This project will combine optical neuroimaging, behavioral, and pharmacological techniques to investigate this learning-induced sensory neuroplasticity. The Specific Aims of the project are 1) to use various fear conditioning paradigms to determine the circumstances under which this sensory neuroplasticity occurs and how it relates to the formation of memories relating the odor and fear-inducing stimuli, 2) to learn the neural mechanisms by which this sensory neuroplasticity occurs, including the circuitry by which information about the fearful associations of CS+ reaches the primary sensory neurons, and 3) to discern how the change in the neural representation of the CS+ alters the brain's representation of sensory input both after normal emotional learning and in a rodent model of PTSD.

DESCRIPTION (provided by applicant): A growing body of scientific literature indicates that sensory processing in the nervous system incorporates not just bottom-up analysis of sensory information that originates from the sensory organs but also top-down expectations about the organization of the sensory world that derive from previous sensory experience. In the olfactory system the first convergence of bottom-up and top-down projections occurs in the glomeruli of the olfactory bulb, where optical imaging techniques now permit the visualization of presynaptic calcium signaling and neurotransmitter release from olfactory receptor neurons (the very first neurons in the olfactory system) in awake mice that are smelling odors and learning about their environment. The olfactory system is thus a uniquely powerful model system to study the synthesis of top-down and bottom-up information. Remarkably, in preliminary experiments we have found that this primary sensory input is strongly modulated by the mouse's expectations about olfactory stimuli, as established by prior sensory experience during the imaging session. For instance, if an odor is always presented after a warning tone cue, the unexpected presentation of that odor without the tone evokes much less presynaptic calcium influx and less neurotransmitter release from the olfactory nerve than when the odor follows the cue. This effect appears to occur via a GABAB receptor-mediated presynaptic inhibition of neurotransmitter release from these synapses. Because the output of the receptor neurons themselves is modulated by expectations, these data suggest that there is actually no purely bottom-up information in the olfactory system at all. This has profound implications for our understanding of neural representations of olfactory stimuli and will inform our understanding of other, less experimentally tractable sensory systems. This proposal confirms and extends these findings by testing the nature of the expectations (e.g. is the expectation odor-specific?), their time course (e.g. are expectation effects anticipatory?), and their neural mechanisms (e.g. are descending projections to the olfactory bulb necessary during the establishment of the expectation or only for detecting unexpected outcomes?). Further experimentation is designed to reveal the perceptual consequences of these neural changes (e.g. do expected odors smell stronger than unexpected odors?) and whether the difference in neurotransmitter release from receptor neurons is necessary for these perceptual effects to occur. Importantly, this work will be designed and analyzed in the context of information theory, a formal theory that allows the quantification of how expected or surprising a given stimulus is and thus provides testable quantitative predictions for assessing the neurophysiological and psychophysical consequences of expectation. These results should provide an essential step in understanding how cognition can play a role in perception as early as the first neurons in a sensory system.

Threatening or aversive stimuli normally evoke healthy fear, in which the brain?s defensive motivational systems drive protective behaviors. When a person or animal learns that a particular sensory stimulus predicts future harm, that stimulus begins to evoke fearful reactions as well. This is called learned fear. Sensory stimuli that are physically similar or conceptually related to the threat-predictive stimulus normally also evoke fear because of the reasonable belief that they might also predict future harm. This is called generalization of learned fear, and it is a normal part of healthy fear. However, many Americans suffer from disordered fear, in which the feeling of acute threat (fear) or potential threat (anxiety) generalizes to inappropriate stimuli and situations that may resemble or be associated with traumatic events but do not actually indicate an impending threat. Figuring out how to limit generalization so that a patient is only fearful in appropriate situations is a key practical challenge for the treatment of anxiety disorders. Most research on the biological basis of anxiety disorders and learned fear has focused on the mechanisms by which the brain learns the initial fear and extrapolates fearful behavior across situations. However, evidence is accumulating that learned fear also evokes profound changes in the brain?s sensory systems. This includes becoming hyper-sensitive and hyper-responsive to threat-predictive stimuli in ways that may underlie common post-traumatic symptoms like hyper-vigilance and attentional bias toward threat-predictive stimuli. In the previous project period we used a mouse model to observe how the neurobiology of the olfactory system is changed during appropriate fear and observed that fear learning makes the olfactory system selectively hyper-responsive to threat-predictive odor, generating a neural ?alarm signal? as early as the sensory input to the brain. In contrast, in this project period we will explore the more clinically- relevant situation of fear generalization, where initial trauma evokes fear of new stimuli that may not actually predict a threat. In preliminary experiments we employed an experimental paradigm in which mice undergo a traumatic experience associated with a particular odor but then generalize their fear across many novel odors. We will test whether this experience causes the olfactory system to become non-selectively hyper-responsive to many dissimilar odors, which might drive downstream responding as if the new odors are dangerous. We will also investigate the neural circuitry by which information about the traumatic event reaches the olfactory system and induces change in the response to many different odors. Finally, we will evaluate multiple candidate approaches to reverse the behavioral and sensory consequences of fear generalization, including comparing conventional exposure (a.k.a. extinction) therapy using the original trauma-associated odor with new therapy paradigms intended to ?refine? the generalized fear either through repeated exposure to novel stimuli or through follow-up fear training in which the trauma is explicitly paired with actually predictive stimuli but not with non- threatening stimuli.