Indiana University-Purdue University Indianapolis (IUPUI) / Early life trauma is a risk factor for a number of neuropsychiatric disorders, including schizophrenia (SZ) and depression. Animal models have played a critical role in understanding how early-life trauma may evoke changes in behavior and biomarkers of altered brain function that resemble these neuropsychiatric disorders. However, since SZ is a complex condition with multifactorial etiology, it is difficult to model the breadth of this condition in a single animal model. Considering this, it is necessary to develop rodent models with clearly defined subsets of pathologies observed in the human condition and their developmental trajectory. Episodic memory is among the cognitive deficits observed in SZ. Theta (6-10 Hz), low gamma (30-50 Hz), and high gamma (50-100 Hz) frequencies in the hippocampus (HC) are critical for encoding and retrieval of memory. Also, theta-gamma comodulation, defined as correlated fluctuations in power between these frequencies, may provide a mechanism for coding episodic sequences by coordinating neuronal activity at timescales required for memory encoding and retrieval. Given that patients with SZ have impaired recognition memory, the overall objectives of these experiments were to assess local field potential (LFP) recordings in the theta and gamma range from the dorsal HC during a recognition memory task in an animal model that exhibits a subclass of symptoms that resemble SZ. In Aim 1, LFPs were recorded from the HC to assess theta and gamma power to determine whether rats that were maternally deprived (MD) for 24-hrs on postnatal day (PND 9), had altered theta and high/low gamma power compared to sham rats during novel object recognition (NOR). Brain activity was recorded while animals underwent NOR on PND 70, 74, and 78. In Aim 2, the effects of theta-low gamma comodulation and theta-high gamma comodulation in the HC were assessed during NOR between sham and MD animals. Furthermore, measures of maternal care were taken to assess if high or low licking/grooming behaviors influenced recognition memory. It was hypothesized that MD animals would have impaired recognition memory and lower theta and low/high gamma power during interaction with both objects compared to sham animals. Furthermore, it was hypothesized that sham animals would have higher theta-gamma comodulation during novel object exploration compared to the familiar object, which would be higher than the MD group. Measures of weight, locomotor activity, and thigmotaxis were also assessed. MD animals were impaired on the NOR task and had no change in theta or low/high gamma power or theta-gamma comodulation when interacting with the novel or familiar object during trials where they performed unsuccessfully or successfully. However, higher theta and gamma power and theta-gamma comodulation was observed in sham animals depending on the object they were exploring or whether it was a successful or unsuccessful trial. These data indicate altered functioning of the HC following MD and a dissociation between brain activity and behavior in this group, providing support that early life trauma can induce cognitive and physiological impairments that are long-lasting. In conclusion, these data identify a model of early life stress with a translational potential, given that there are points of contact between human studies and the MD model. Furthermore, these data provide a set of tools that could be used to further explore how these altered neural mechanisms may influence cognition and behavior.

Encoding and consolidation of memories are two processes within the hippocampus, and connected cortical networks, that recruit different circuit level dynamics to effectively process and pass information from brain region to brain region. In the hippocampal CA1 pyramidal layer local field potential (LFP), these processes take the form of theta and sharp wave ripples (SPW-Rs) for encoding and consolidation, respectively. As an animal runs through an environment, neurons become active at specific locations in the environment (place cells) increasing their firing rate, functionally representing these specific locations. These firing rate increases are organized within the local theta oscillations and sequential activation of many place cells creates a map of the environment. Once the animal stops moving and begins consummatory behaviors, such as eating, drinking, or grooming, theta activity diminishes, and large irregular activity (LIA) begins to dominate the LFP. Spontaneously, with the LIA, the place cells active during the experience are replayed during SPW-Rs in the same spatial order they were encountered in the environment. Both theta and SPW-R oscillations and their associated neuronal firing are necessary for effective place recognition as well as learning and memory. As such, interruption or termination of SPW-R events results in decreased learning performance over days. During exploration, the associated theta and sequential place cell activity is thought to encode the experience. During quiet restfulness or slow wave sleep (SWS), SPW-R events, that replay experience specific place sequences, are thought to be the signal by which systems consolidation progresses and the hippocampus guides cortical synaptic reorganization. The granular retrosplenial cortex (gRSC) is an associational area that exhibits high frequency oscillations (HFOs) during both hippocampal theta and SPW-Rs, and is potentially a period when the gRSC interprets incoming content from the hippocampus during encoding and systems consolidation. However, the precise laminar organization of synaptic currents supporting HFOs, whether the local gRSC circuitry can support HFOs without patterned input, and the precise coupling of hippocmapla oscillations to gRSC HFOs across brain states remains unknown. We aimed to answer these questions using in vivo, awake electrophysiological recordings in head-fixed mice that were trained to run for water rewards in a 1D virtual environment. We show that gRSC synaptic currents supporting HFOs, across all awake brain states, are exclusively localized to layer 2/3 (L2/3), even when events are detected within layer 5 (L5). Using focal optogenetics, both L2/3 and L5 can generate induced HFOs given a strong enough broad stimulation. Spontaneous gRSC HFOs occurring outside of SPW-Rs are highly comodulated with medial entorhinal cortex (MEC) generated high gamma in hippocampal stratum lacunosum moleculare. gRSC HFOs may serve a necessary role in communication between the hippocampus during SPW-Rs states and between the hippocampus, gRSC, and MEC during theta states to support memory consolidation and memory encoding, respectively. / Doctor of Philosophy / As an animal moves through an environment, individual neurons in the hippocampus, known as place cells, increase and decrease their firing rate as the animal enters and exits specific locations in the environment. Within an environment, multiple neurons become active in different locations, this cooperation of spiking in various locations creates a place map of the environment. Now let's say when the animal moved from one corner of the environment to another, place cells 'A', 'C', 'B', 'E', and 'D' became active in that order. This means, at any given point in the environment, the animal is standing in a venn-diagram-esque overlap of place fields, or locations individual place cells represent. A key question that entranced researchers for many years was how do these neurons know when to be active to not impinge on their neighbor's locations? The answer to this question rested with population electrical activity, known as the local field potential (LFP), that place cell activity is paced to. During active navigation through an environment, place cells activity is coupled to the phase of a slow ~8 hertz (Hz) theta oscillation. Within one theta cycle, or peak to peak, multiple place cells are active, representing the venn diagram of location the animal is in. Importantly, this theta activity and encoding of place cell activity is largely seen during active running or rapid eye movement (REM) sleep. During slow wave sleep (SWS), after an animal has experienced a specific environment and has created a place map, place cells are reactivated in the same order the animal experienced them in. From our previous example, the content of this reactivation would be the place cells 'A', 'C', 'B', 'E', and 'D' which all would be reactivated in that same order. These reactivations or replays occur during highly synchronous and fast LFP oscillations known as sharp wave-ripples (SPW-Rs). SPW-Rs are thought to be a key LFP event that drives memory consolidation and the eventual conversion of short-term memory into long-term memory. However, for consolidation to occur, connected cortical regions need to be able to receive and interpret the information within SPW-Rs. The granular retrosplenial cortex (gRSC) is one proposed region that serves this role. During SPW-Rs the superficial gRSC has been shown to exhibit high frequency oscillations (HFOs), which potentially serve the purpose for interpreting SPW-R content. However, HFOs have been reported during hippocampal theta, suggesting HFOs serve multiple purposes in interregional communication across different states. In this study, we found that naturally occurring gRSC HFOs occur exclusively in layer 2/3 across all awake brain states. Using focal optogenetic excitation we were able to evoke HFOs in both layer 2/3 and 5. Spontaneous gRSC HFOs occurring without SPW-Rs were highly comodulated with medial entorhinal cortex (MEC) generated high gamma in hippocampal stratum lacunosum moleculare. gRSC HFOs may serve a general role in supporting hippocampo-cortical dialogue during SPW-R and theta brain states to support memory consolidation and encoding, respectively.

<pre><p>Difficulty understanding speech in background noise is the most common hearing complaint. Elucidating the neurophysiological mechanisms underlying speech intelligibility in everyday environments with multiple sound sources and distortions is hence important for any technology that aims to improve real-world listening. Using a combination of behavioral, electroencephalography (EEG), and computational modeling experiments, this dissertation provides insight into how the brain analyzes such complex scenes, and what roles different acoustic cues play in facilitating this process and in conveying phonetic content. Experiment #1 showed that brain oscillations selectively track the temporal envelopes (i.e., modulations) of attended speech in a mixture of competing talkers, and that the strength and pattern of this attention effect differs between individuals. Experiment #2 showed that the fidelity of neural tracking of attended-speech envelopes is strongly shaped by the modulations in interfering sounds as well as the temporal fine structure (TFS) conveyed by the cochlea, and predicts speech intelligibility in diverse listening environments. Results from Experiments #1 and #2 support the theory that temporal coherence of sound elements across envelopes and/or TFS shapes scene analysis and speech intelligibility. Experiment #3 tested this theory further by measuring and computationally modeling consonant categorization behavior in a range of background noises and distortions. We found that a physiologically plausible model that incorporated temporal-coherence effects predicted consonant confusions better than conventional speech-intelligibility models, providing independent evidence that temporal coherence influences scene analysis. Finally, results from Experiment #3 also showed that TFS is used to extract speech content (voicing) for consonant categorization even when intact envelope cues are available. Together, the novel insights provided by our results can guide future models of speech intelligibility and scene analysis, clinical diagnostics, improved assistive listening devices, and other audio technologies.</p></pre>