CA1-projecting subiculum neurons facilitate object-place learning.

Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. Here we show that the afferent circuitry of CA1-projecting subicular neurons is biased by inputs from CA1 inhibitory neurons and the visual cortex, but lacks input from the entorhinal cortex. Efferents of the CA1-projecting subiculum neurons also target the perirhinal cortex, an area strongly implicated in object-place learning. We identify a critical role for CA1-projecting subicular neurons in object-location learning and memory, and show that this projection modulates place-specific activity of CA1 neurons and their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from the visual cortex, reach the hippocampal output region CA1. Our findings also implicate this circuitry in the formation of complex spatial representations and learning of object-place associations

Functional interactions between the hippocampus, medial entorhinal cortex and medial prefrontal cortex for spatial and nonspatial processing

Memory formation and recall depend on a complex circuit that includes the hippocampus and associated cortical regions. The goal of this thesis was to understand how two of the cortical connections, the medial entorhinal cortex (MEC) and medial prefrontal cortex (mPFC), influence spatial and nonspatial activity in the hippocampus. Cells in the MEC exhibit prominent spatially selective activity and have been hypothesized to drive place representation in the hippocampus. In Experiment 1 the MEC was transiently inactivated using the inhibitory opsin ArchaerhodopsinT (ArchT), and simultaneous recordings from CA1 were made as rats ran on an elliptical track. In response to MEC disruption some cells in the hippocampus shifted the preferred location of activity, some changed firing rate and others were unaffected. The new representation that developed following MEC disruption remained stable despite the fact that inhibition was transient. If the MEC is the source of spatial activity in the hippocampus the activity would be either time-locked to periods of inhibition or unstable throughout the period of inconsistent input. These results show that the MEC guides spatial representation in the hippocampus but does not directly drive spatial firing. The mPFC is generally thought to guide behavior in response to contextual elements. Experiment 2 examined the interaction between the mPFC and the hippocampus as rats performed a contextual discrimination task. Recordings were made in CA1, and the mPFC was disrupted using ArchT during the odor sampling phase of the discrimination. As animals perform this task neurons in the hippocampus respond to a conjunction of odor and location which indicates an association of what and where information in the hippocampus. Optogenetic disruption of the mPFC led to a decrease in nonspatial representation. Individual cells showed lower levels of odor selectivity, but there was no change in the level of spatial representation. This indicates that the mPFC is important for determining how the hippocampus represents nonspatial information but does not alter the spatial representation. The results are discussed within a model of memory formation that includes binding spatial and nonspatial information in the hippocampus

Recent Advances in Graph Partitioning

We survey recent trends in practical algorithms for balanced graph partitioning together with applications and future research directions

The Role of the Hippocampus in Representations of Emotional Memory

Although the hippocampus has long been implicated in contextual fear learning, the exact function of this brain structure is unclear. It is generally thought to encode a spatial context with which a fear memory can be associated, but how it may accomplish this and whether it plays a role in emotional memory is largely unknown. It is also unclear whether the hippocampus acts as a single unitary structure, or whether the dorsal and ventral poles, which exhibit differential connectivity to other brain regions, function independently. This dissertation examines the involvement of the hippocampus in emotional learning. A contextual fear conditioning paradigm using a predator odor as an ethologically relevant fearful stimulus was developed and lesions and immunohistochemistry were used to examine differential involvement of the dorsal and ventral hippocampus in response to fear learning. Long-term physiological recordings of dorsal place cells were then conducted to determine the effects of fear conditioning and also fear extinction on contextual representations in the hippocampus. Additionally, cells in the ventral hippocampus were assessed for responses to visuospatial manipulations and changing odor cues of varying emotional valence. It was found that the dorsal and ventral hippocampal regions are both independently required for contextual fear conditioning, and neurons in each region are differentially activated in response to fear learning. Furthermore, place cells in the dorsal hippocampus remapped in response to fear conditioning and stabilized those new fields in the long term. Extinction training caused many place cells to remap once again, suggesting that the dorsal hippocampus encodes varying representations of `fearful\u27 and `safe\u27 contexts. Finally, cells in the ventral hippocampus exhibited stronger responses to anxiogenic contextual cues compared to dorsal cells. In conclusion, these data suggest that the hippocampus is involved in emotional learning and that its function may vary along its longitudinal axis

Molecular Mechanisms Responsible for Functional Cortical Plasticity During Development and after Focal Ischemic Brain Injury

The cerebral cortex is organized into functional representations, or maps, defined by increased activity during specific tasks. In addition, the brain exhibits robust spontaneous activity with spatiotemporal organization that defines the brain’s functional architecture (termed functional connectivity). Task-evoked representations and functional connectivity demonstrate experience-dependent plasticity, and this plasticity may be important in neurological development and disease. An important case of this is in focal ischemic injury, which results in destruction of the involved representations and disruption of functional connectivity relationships. Behavioral recovery correlates with representation remapping and functional connectivity normalization, suggesting functional organization is critical for recovery and a potentially valuable therapeutic target. However, the cellular and molecular mechanisms that drive this systems-level plasticity are unknown, making it difficult to approach therapeutic modulation of functional brain organization. Using cortical neuroimaging in mice, this dissertation explores the role of specific genes in sensory deprivation induced functional brain map plasticity during development and after focal ischemic injury. In the three contained chapters, I demonstrate the following: 1) Arc, an excitatory neuron synaptic-plasticity gene, is required for representation remapping and behavioral recovery after focal cortical ischemia. Further, perilesional sensory deprivation can direct remapping and improve behavioral recovery. 2) Early visual experience modulates functional connectivity within and outside of the visual cortex through an Arc-dependent mechanism. 3) Electrically coupled inhibitory interneuron networks limit spontaneous activity syncrhony between distant cortical regions. This work starts to define the molecular basis for plasticity in functional brain organization and may help develop approaches for therapeutic modulation of functional brain organization

Exteroceptive and interoceptive cue control of hippocampal place cells

Place cells in the hippocampal formation form the cornerstone of the rat’s navigational system and together with head direction cells in the postsubiculum and grid cells in the entorhinal cortex are the key elements of what O’Keefe and Nadel (1978) postulate to be a “cognitive map”. The hippocampal formation is ideally positioned anatomically to receive highly processed inputs from almost all brain regions. Previous research has focused on the cues that determine and contribute to place cell selectivity. Such cues include information about the external world that the rat perceives through its senses (“exteroceptive cues”) as well as cues internal to the body such as proprioception or somatosensation (“interoceptive cues”). This thesis uses a novel experimental paradigm in which the rat runs on a moving-treadmill linear track to investigate the relative contribution of interoceptive and exteroceptive cues for determining place cell spatial selectivity. The major finding is that place fields shift in the direction of the moving treadmill, both when the animal runs along with or against the motion of the treadmill, indicating that self-motion information is a key input to place cells. Furthermore, place fields in the middle of the track shift more than fields closer to the end walls suggesting that exteroceptive information interacts with interoceptive information to assist in accurate navigation. This conclusion is further supported by experiments performed in complete darkness where two populations of cells are observed: the first are cells which become quiescent or remap, presumably under strong exteroceptive control, while the second are cells that maintain similar firing characteristics under both lighting conditions, putatively under the influence of interoceptive inputs

From Rapid Place Learning to Behavioral Performance: A Key Role for the Intermediate Hippocampus

Rapid place encoding by hippocampal neurons, as reflected by place-related firing, has been intensely studied, whereas the substrates that translate hippocampal place codes into behavior have received little attention. A key point relevant to this translation is that hippocampal organization is characterized by functional-anatomical gradients along the septotemporal axis: Whereas the ability of hippocampal neurons to encode accurate place information declines from the septal to temporal end, hippocampal connectivity to prefrontal and subcortical sites that might relate such place information to behavioral-control processes shows an opposite gradient. We examined in rats the impact of selective lesions to relevant parts of the hippocampus on behavioral tests requiring place learning (watermaze procedures) and on in vivo electrophysiological models of hippocampal encoding (long-term potentiation [LTP], place cells). We found that the intermediate hippocampus is necessary and largely sufficient for behavioral performance based on rapid place learning. In contrast, a residual septal pole of the hippocampus, although displaying intact electrophysiological indices of rapid information encoding (LTP, precise place-related firing, and rapid remapping), failed to sustain watermaze performance based on rapid place learning. These data highlight the important distinction between hippocampal encoding and the behavioral performance based on such encoding, and suggest that the intermediate hippocampus, where substrates of rapid accurate place encoding converge with links to behavioral control, is critical to translate rapid (one-trial) place learning into navigational performance

Digital signal processing for segmented HPGe detectors preprocessingalgorithms and pulse shape analysis

MINIBALL is an versatile spectrometer consisting of 24 longitudinally six-fold segmented HPGe detectors, build for the efficient detection of rare γ decays in nuclear reactions of radioactive ion beams. MINIBALL was the first spectrometer equipped with digital electronics. Pulse shape analysis algorithms to determine the interaction position of γ -rays were implemented on a Digital Signal Processor and validated in an experiment using a collimated γ -ray source. Emphasis was placed on the properties of the different digital signal processing algorithms, the consequences for the implementation and the applicability for position determination. The next generation of γ -ray spectrometers will consist of highly segmented HPGe detectors equipped with digital electronics, resulting in a more than ten-fold increase in complexity compared to current spectrometers. To enable the construction of a γ -ray tracking spectrometer, new and powerful digital electronics will be developed. Preprocessing algorithms, giving the γ -ray energy and generating event triggers, were implemented on a VME module equipped with fast A/D converters and tested with different detectors and sources. Emphasis was placed on the detailed simulation and understanding of the algorithms as well as the influence of electronics and detector onto the energy resolution

Micro-, Meso- and Macro-Dynamics of the Brain

Neurosciences, Neurology, Psychiatr