Joshua Craig Brumberg - US grants

For many years it has been known that different states of arousal can be classified based upon the predominant frequency of neural oscillations observed in electroencephalograms. The emergence of gamma-band oscillations (30-70Hz) is a hallmark of the transition from sleep states to states of arousal. It is proposed that a subclass of supragranular pyramidal cells, chattering cells, which discharge high frequency action potentials (greater than 250Hz) with interburst intervals in the gamma-band range are important in the generation of neocortical gamma-band oscillations. Preliminary in vitro work has shown that a sub- class of pyramidal neurons can be induced to discharge of action potentials that chattering cells by injection of depolarizing current. The onset of gamma-band oscillations following electrical stimulation of reticular formation activating centers will be assessed in vivo, via intracellular recordings from burst generating neurons and the monitoring of local field potentials in the supragranular layers of cat primary visual cortex. In vitro depolarizing current and the application of cholinergic agonists will be used to study the genesis of burst firing and the biophysical changes that the neuron undergoes when it switches form firing single action potentials to bursts of action potentials. By employing both in vivo and in vitro recording methodologies the role that burst generating neurons have in the development of neuronal synchronization and gamma-band oscillations will assessed.

The neocortex constitutes the largest component of the brain in mammals and is the primary site of mental functions. Crucial to its functionality are the interactions between distinct neuronal networks within the cortex. No unitary theory of how the cortex works exists, although it is clear that understanding its microcircuit is necessary to discern its computational capabilities. Anatomical and physiological studies have suggested that the connectivity of the cortical microcircuitry is complex, but not random. It is clear that inhibitory neurons target their connections extremely specifically. Less is known about the pyramidal-pyramidal connections that constitutes the `skeleton' of the cortex. A variety of anatomical and physiological experiments have highlighted the fact that there is heterogeneity among pyramidal cells in both their morphologies and response properties. It is conceivable that their interconnections are also precise and that the neocortex, like the retina, may be composed of dozens or hundreds of classes of neurons with specialized circuit functions. A major limitation of past work using traditional in vivo and in vitro recording techniques is the difficulty in revealing functional connections in large numbers. Furthermore, it is difficult to know with a high degree of certainty what type of neuron is being recorded from, for instance; is it a local circuit neuron or is it a cortical-fugal neuron? Finally, it is difficult to determine what network a specific neuron is incorporated within. These limitations have slowed our understanding of the connectivity patterns of the cortical microcircuit. To overcome these limitations fluorescent beads will be retrogradely transported back to independent networks of pyramidal cells located in layer VI of the primary somatosensory cortex, following injections into the ipsilateral motor cortex and/or the ventral posterior nucleus of the thalamus of mice. Fluorescent optics will facilitate the targeting of specific classes of neurons. Thalamocortical slices will be prepared from these animals for electrophysiological recordings and optical imaging of network activity using calcium indicators. By combining optical, fluorescent and electrophysiological techniques we will be able to both image the activity of an entire local circuit as well as record the activity of individual elements in the circuit during ongoing and stimulus driven network activity. The results of this study will further our understanding of the different classes of pyramidal cells and how they are connected as well as how the circuits anatomical connectivity affects is functionality. Gaining insight into the functioning of the cortical circuit can pave the way towards an understanding of fundamental physiological processes involved in information processing and how the disruption of the microcircuit by pathophysiological processes (e.g. schizophrenia) works, and thus possibly lead towards the development of new therapeutic interventions.

[unreadable] DESCRIPTION (provided by applicant): The Barrels meeting is the longest running (now in its 20th year) satellite meeting to the annual Society for Neuroscience Meeting. The meeting focuses on the anatomy, physiology and behavior of the rodent whisker-to-barrel system. The meeting serves as a catalyst for interactions between researchers in different laboratories and different scientific fields. Meeting attendance averages over 125 attendees annually with the majority being graduate students and post-doctoral fellows. This years meeting will be held at the Museum of Contemporary Art San Diego - La Jolla campus's Sherwood Auditorium and the poster session will be held next door at the La Jolla Women's Club. The whisker- to-barrel pathway has become one of the most utilized model systems in Neuroscience for those interested in development, sensory coding and behavioral studies. The Barrels meeting is arranged around general themes which this year includes: the role of cortical inhibitory circuits, molecular development of the barrel system and synaptic plasticity in the barrel system. For each theme there will be three or four invited presentations (30 min) delivered by established researchers, followed by 4-6 shorter (15 min) talks by more junior researchers and graduate students. In addition there is a poster session (typically 50-60 posters are presented annually). This mix of long and short talks and poster presentations provides ample opportunity for new researchers to present their findings to an international audience of scientific peers. The Barrels meeting consistently encourages researchers to use the Barrels as a model system to explore behavior, development, sensory and motor function. Each year, the Barrels meeting invite's individuals from outside the "Barrels community" to present their research in order to expose the community to new and exciting developments. This year, for example, we have invited Ed Lein from the Allen Brain Sciences Institute to talk about the mouse genome. The Barrels meeting is held just prior to the annual Society for Neuroscience meeting which allows researchers to conveniently attend both meetings consecutively without having to make additional travel plans. The whisker-to-barrel system is one of the most widely utilized model systems in modern neuroscience and the Barrels Meeting provides a forum for investigators using different techniques and studying different aspects of the system to come together and interact in meaningful dialogue which is uncommon at larger more fragmented meetings. The Barrels Meeting is the longest running satellite meeting to the annual Society for Neuroscience Meeting, now in its 20th year. The meeting program is composed if long talks (30 min) by established researchers and shorter talks by more junior individuals (15 min) and a poster session. [unreadable] [unreadable] [unreadable]

The proposed research will test the novel hypothesis that enhanced blood supply to a local brain region impacts neural processing. A key feature of neural circuits is their flexibility, their ability to respond differently (for example, to a sensory stimulus) depending on context. This flexibility allows organisms in general and humans in particular to perform crucial tasks for survival, such as shifting attention. This flexibility is also crucial to brain health: Failures in normal mechanisms of neural dynamics?in the normal ability to shift sensitivity?have been implicated in diseases ranging from epilepsy to schizophrenia.

In this project the PIs will test the prediction that changes in blood supply to cortical sensory neurons can modulate their responses to sensory inputs. To test this hypothesis, they will integrate four techniques, bringing together expertise from two laboratories: whole animal electrophysiological and imaging studies to define the effect of changes in blood flow on neural activity and electrophysiological and imaging studies in brain slices to begin to investigate the mechanisms underlying this phenomenon. A key feature of the proposed research is development of a novel means of bidirectional blood flow regulation, the viral transfection of light-activated channels into smooth muscle. By constricting or relaxing smooth muscles using directed light, they will expand or contract local cerebral arterioles, regulating blood supply. This method provides an approach independent of the potential confounds of pharmacological intervention.

A second key feature of the proposed research is a summer research initiative for Queens College students at MIT. This program will provide a unique opportunity for Queens College students to experience the MIT environment, systematic training in research proposal development, execution of this plan, training in research ethics, and writing a summary for publication.

DESCRIPTION (provided by applicant): The Barrels meeting is the longest running (now in its 24th year) satellite meeting to the annual Society for Neuroscience Meeting. The meeting focuses on the anatomy, development, physiology, pathology and behavior of the rodent whisker-to-barrel system. The meeting serves as a catalyst for interactions between researchers in different laboratories and different scientific fields. Meeting attendance averages over 125 attendees annually with the majority being graduate students and post-doctoral fellows. The 2011 meeting will be held at the Charles Commons on the Homewood campus of Johns Hopkins University. The whisker-to-barrel pathway has become one of the most utilized model systems in Neuroscience for those interested in development, plasticity, sensory coding and behavioral studies. The Barrels meeting is annually arranged around general themes which bring together speakers utilizing different techniques to answer related questions. For each theme there will be three or four invited presentations (30 min) delivered by established researchers, followed by 4-6 shorter (15 min) talks by more junior researchers and graduate students. In addition there is a poster session (typically 50-60 posters are presented annually) and a data blitzes (5 min talks) for the latest results. This mix of long and short talks and poste presentations provides ample opportunity for new researchers to present their findings to an international audience of scientific peers. The Program Committee works via invitation of the invited speakers and selection of the short talks to maximize geographical, ethnic, career level and gender diversity. The Barrels meeting consistently encourages researchers to use the Barrels as a model system to explore behavior, development, sensory and motor function as well as a model to understand clinical disorders. Each year, the Barrels meeting invite's individuals from outside the "Barrels community" to present their research in order to expose the community to new and exciting developments. The Barrels meeting is held just prior to the annual Society for Neuroscience meeting which allows researchers, especially trainees to conveniently attend both meetings consecutively without having to make additional travel plans. PUBLIC HEALTH RELEVANCE: The Barrels meeting is the longest running (now in its 24th year) satellite meeting to the annual Society for Neuroscience Meeting. The meeting focuses on the anatomy, development, physiology and behavior of the rodent whisker-to-barrel system as model to understand brain functioning under normal and pathological conditions. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

Abstract Sensory deprivation from mice to man has been shown to have profound impacts on neuronal physiology, behavior and cognitive processes. Underling these changes are alterations in neuronal and non-neuronal structures. Our preliminary data shows that following one month of whisker trimming induced sensory deprivation the perineuronal net (PN), a neuron specific form of the extra cellular matrix, is significantly reduced in the barrel cortex of mice. The loss of the PN is most prominent around fast-spiking parvalbumin positive GABAergic interneurons. Converging evidence has shown that fast-spiking interneurons play a pivotal role in the closure of the developmental critical period in the visual system and their proper functioning is necessary for the proper physiological functioning of the cortex. Coincident with deprivation induced decreases in the PN we observed increases in the enzyme tissue plasminogen activator (tPA) which dissolves the PN. Under the same conditions microglia become activated, thus we propose that sensory deprivation induces microglia activation which release tPA and thus decrease the PN. In Aim 1 we will demonstrate a causal link between sensory deprivation, microglia activation and tPA release resulting in PN decreases using immunocytochemical techniques in conjunction with stereology. In Aim 2 we will focus on the physiological roll PNs have in modifying the intrinsic and synaptic properties of fast-spiking interneurons. We will employ our novel small volume incubator which allows for time dependent degradation of the PN in conjunction with dual whole-cell recordings.