Acute silencing of hippocampal CA3 reveals a dominant role in place field responses.

Neurons in hippocampal output area CA1 are thought to exhibit redundancy across cortical and hippocampal inputs. Here we show instead that acute silencing of CA3 terminals drastically reduces place field responses for many CA1 neurons, while a smaller number are unaffected or have increased responses. These results imply that CA3 is the predominant driver of CA1 place cells under normal conditions, while also revealing heterogeneity in input dominance across cells

On the Origin of Hippocampal Ensemble Activity: Neural Mechanisms for Sharp-Wave Ripples and Place Cell Responses

Our cognition is heavily dependent on our ability to form memories out of our experiences. The hippocampus is necessary for the formation of new memories and their retrieval for planning our future behavior. Hippocampal area CA1 local field potential (LFP) exhibits high frequency (100- 250 Hz) events known as sharp-wave ripples (SWRs). These events that occur during slow-wave sleep and awake restfulness have been shown to be important for the consolidation of spatial memory. During exploration, CA1 pyramidal cells, which receive excitatory inputs from entorhinal cortex (EC) and hippocampal area CA3, show location-specific activity known as place fields. However, the mechanism of formation of SWRs and place fields in the presence of these two inputs is not yet well understood. Using high-density multi-tetrode recording and reversible optogenetic manipulation, I found that the silencing of hippocampal area CA3’s Schafer collateral (SC) projections to CA1 decimates SWRs. Furthermore, SC silencing substantially suppresses hippocampal place cell activity during exploration but does not change the position of place fields. Moreover, temporal coding in CA1 place cells, as reflected in their theta phase precession ability, remains intact without CA3 input. These findings shed light on the functional interconnections between hippocampal subregions that support episodic memory. Hippocampal structure and function is disrupted in several psychiatric disorders such as schizophrenia. The calcineurin mouse model of schizophrenia whose synaptic activity is impaired by deleting the calcineurin phosphatase gene in its forebrain shows behavioral and cognitive abnormalities recapitulating symptoms of schizophrenia and is therefore a good candidate for examining hippocampal neural circuit dysfunctions. Using multi-tetrode recording, we found that CA1 SWRs in these mice become overabundant and the reactivation of place cells during SWRs is abolished. However, place cells preserve their normal activity during exploration. This selective disruption in SWRs provides a mechanism for underlying impairments in information processing that may contribute to the cognitive impairments in schizophrenia. Overall, the research and technical advances described in this dissertation represent a step towards understanding hippocampal neural ensemble activity as is reflected in SWRs and place cell responses

Acute silencing of hippocampal CA3 reveals a dominant role in place field responses.

Neurons in hippocampal output area CA1 are thought to exhibit redundancy across cortical and hippocampal inputs. Here we show instead that acute silencing of CA3 terminals drastically reduces place field responses for many CA1 neurons, while a smaller number are unaffected or have increased responses. These results imply that CA3 is the predominant driver of CA1 place cells under normal conditions, while also revealing heterogeneity in input dominance across cells

The functional organization of excitatory synaptic input to place cells.

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations

Impaired Hippocampal Ripple-Associated Replay in a Mouse Model of Schizophrenia

The cognitive symptoms of schizophrenia presumably result from impairments of information processing in neural circuits. We recorded neural activity in the hippocampus of freely behaving mice that had a forebrain-specific knockout of the synaptic plasticity- mediating phosphatase calcineurin and were previously shown to exhibit behavioral and cognitive abnormalities, recapitulating the symptoms of schizophrenia. Calcineurin knockout (KO) mice exhibited a 2.5-fold increase in the abundance of sharp-wave ripple (SWR) events during awake resting periods and single units in KO were overactive during SWR events. Pairwise measures of unit activity, however, revealed that the sequential reactivation of place cells during SWR events was completely abolished in KO. Since this relationship during postexperience awake rest periods has been implicated in learning, working memory, and subsequent memory consolidation, our findings provide a mechanism underlying impaired information processing that may contribute to the cognitive impairments in schizophrenia.RIKEN Brain Science InstituteAlfred P. Sloan Foundation (Fellowship)Brain & Behavior Research Foundation (NARSAD Young Investigator Award)National Institutes of Health (U.S.) (NIH grant MH78821)National Institutes of Health (U.S.) (NIH grant MH58880)National Institutes of Health (U.S.) (NIH grant MH086702

Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.

Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local circuit activity to the diametric regulation of two critical early phases of adult hippocampal neurogenesis