Hippocampal Theta Research Articles

Supramammillary Theta Oscillations in Water Maze Learning.

The supramammillary nucleus (SuM) in the hypothalamus, in conjunction with the hippocampus (HPC), has been implicated through theta oscillations in various brain functions ranging from locomotion to learning and memory. While the indispensable role of the SuM in HPC theta generation in anesthetized animals is well-characterized, the SuM is not always necessary for HPC theta in awake animals. This raises questions on the precise behavioral relevance of SuM theta activity and its interaction with HPC theta activity. We used simultaneously recorded SuM and HPC local field potentials (LFPs) in a one-day water maze (WM) learning paradigm in rats (n = 8), to show that theta activities recorded from the SuM itself were not positively correlated with locomotor (swimming) speed nor acceleration, but the individual relationship between acceleration and SuM theta frequency is correlated with WM learning rates. In contrast, we found that SuM-HPC theta phase coherence is strongly correlated with swimming speed and acceleration, but these do not relate to WM learning. SuM-HPC-directed coherence analysis demonstrated no swimming kinetics nor learning rate associations, but revealed that periods of high SuM-HPC theta phase coherence are driven by the SuM at relatively low (~6.2 Hz) frequencies. Additionally, we demonstrate that the SuM and the HPC also engage in non-random, non-coherent phase coupling modes where either structure preferentially displays a ± 2 Hz difference with the other. Our data indicate SuM theta LFPs do not appear to be related to either speed coding or spatial learning in swimming rats and display non-random out-of-phase theta frequency coupling with the HPC.

Spatial maps in piriform cortex during olfactory navigation.

Odors are a fundamental part of the sensory environment used by animals to inform behaviors such as foraging and navigation1,2. Primary olfactory (piriform) cortex is thought to be dedicated to encoding odor identity3-8. Here, using neural ensemble recordings in freely moving rats performing a novel odor-cued spatial choice task, we show that posterior piriform cortex neurons also carry a robust spatial map of the environment. Piriform spatial maps were stable across behavioral contexts independent of olfactory drive or reward availability, and the accuracy of spatial information carried by individual neurons depended on the strength of their functional coupling to the hippocampal theta rhythm. Ensembles of piriform neurons concurrently represented odor identity as well as spatial locations of animals, forming an "olfactory-place map". Our results reveal a previously unknown function for piriform cortex in spatial cognition and suggest that it is well-suited to form odor-place associations and guide olfactory cued spatial navigation.

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice.

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

The posterior hypothalamic area as an independent generator of rhythmic theta oscillatory activity

Theta rhythm is one of the most prominent examples of rhythmic oscillatory activity in mammalian brain and it is generated mainly in structures of the limbic cortex, including the hippocampal formation. In the 1970s it was shown that theta rhythm may be also recorded in diencephalic region including the posterior hypothalamic nuclei and supramammillary nucleus, together considered as the posterior hypothalamic area (PHa). For decades it was stated that local posterior hypothalamic oscillatory activity is controlled by the descending inputs going to the PHa from the septohippocampal system. However, the latest studies indicated that theta rhythm can be recorded in deafferented PHa in vitro preparations which indicates that the posterior hypothalamic area should be considered as an independent of the other brain structures theta generator. In subsequent research the neurochemical and cellular basis of PHa theta were examined in both in vivo and in vitro conditions. In the light of multiple evidence obtained in these studies, it is the author’s intent to summarize the data concerning the role of the posterior hypothalamic area in hippocampal theta rhythm generation as well as the ability of that brain structure to independently generate theta rhythmicity.

Modification of pre-ictal cortico-hippocampal oscillations by medial ganglionic eminence precursor cells grafting in the pilocarpine model of epilepsy

Cell replacement therapies using medial ganglionic eminence (MGE)-derived GABAergic precursors reduce seizures by restoring inhibition in animal models of epilepsy. However, how MGE-derived cells affect abnormal neuronal networks and consequently brain oscillations to reduce ictogenesis is still under investigation. We performed quantitative analysis of pre-ictal local field potentials (LFP) of cortical and hippocampal CA1 areas recorded in vivo in the pilocarpine rat model of epilepsy, with or without intrahippocampal MGE-precursor grafts (PILO and PILO+MGE groups, respectively). The PILO+MGE animals had a significant reduction in the number of seizures. The quantitative analysis of pre-ictal LFP showed decreased power of cortical and hippocampal delta, theta and beta oscillations from the 5 min. interictal baseline to the 20 s. pre-ictal period in both groups. However, PILO+MGE animals had higher power of slow and fast oscillations in the cortex and lower power of slow and fast oscillations in the hippocampus compared to the PILO group. Additionally, PILO+MGE animals exhibited decreased cortico-hippocampal synchrony for theta and gamma oscillations at seizure onset and lower hippocampal CA1 synchrony between delta and theta with slow gamma oscillations compared to PILO animals. These findings suggest that MGE-derived cell integration into the abnormally rewired network may help control ictogenesis.

Optimizing real-time phase detection in diverse rhythmic biological signals for phase-specific neuromodulation.

Closed-loop, phase-specific neurostimulation is a powerful method to modulate ongoing brain activity for clinical and research applications. Phase-specific stimulation relies on estimating the phase of an ongoing oscillation in real time and issuing a control command at a target phase. Phase detection algorithms based on Fast Fourier transform (FFT) are widely used due to their computational efficiency and robustness. However, it is unclear how algorithm performance depends on the spectral properties of the input signal and how algorithm parameters can be optimized. We used offline simulation to evaluate the performance of three algorithms (endpoint-corrected Hilbert Transform, Hilbert Transform and phase mapping) on three rhythmic biological signals with distinct spectral properties (rodent hippocampal theta potential, human EEG alpha and human essential tremor). First, we found that algorithm performance was more strongly influenced by signal amplitude and frequency variation compared with signal to noise ratio. Second, our simulations showed that the size of the data window for phase estimation was critical for the performance of FFT-based algorithms, where the optimal data window corresponds to the period of the oscillation. We validated this prediction with real time phase detection of hippocampal theta oscillations in freely behaving rats performing spatial navigation. Our findings define the relationship between signal properties and algorithm performance and provide a convenient method for optimizing FFT-based phase detection algorithms.

Rat anterior cingulate neurons responsive to rule or strategy changes are modulated by the hippocampal theta rhythm and sharp-wave ripples.

To better understand neural processing during adaptive learning of stimulus-response-reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y-maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule-change responsive neurons (70%), but other neurons that were correlated with strategy-change, strategy value and reward-rate were not. However, hippocampal sharp wave-ripples modulated significantly higher proportions of rule-change, strategy-change and reward-rate responsive cells during post-session sleep but not pre-session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged.

Predictive grid coding in the medial entorhinal cortex.

The entorhinal cortex represents allocentric spatial geometry and egocentric speed and heading information required for spatial navigation. However, it remains unclear whether it contributes to the prediction of an animal's future location. We discovered grid cells in the medial entorhinal cortex (MEC) that have grid fields representing future locations during goal-directed behavior. These predictive grid cells represented prospective spatial information by shifting their grid fields against the direction of travel. Predictive grid cells discharged at the trough phases of the hippocampal CA1 theta oscillation and, together with other types of grid cells, organized sequences of the trajectory from the current to future positions across each theta cycle. Our results suggest that the MEC provides a predictive map that supports forward planning in spatial navigation.

Imaging high-frequency voltage dynamics in multiple neuron classes of behaving mammals.

Fluorescent genetically encoded voltage indicators report transmembrane potentials of targeted cell-types. However, voltage-imaging instrumentation has lacked the sensitivity to track spontaneous or evoked high-frequency voltage oscillations in neural populations. Here we describe two complementary TEMPO voltage-sensing technologies that capture neural oscillations up to ~100 Hz. Fiber-optic TEMPO achieves ~10-fold greater sensitivity than prior photometry systems, allows hour-long recordings, and monitors two neuron-classes per fiber-optic probe in freely moving mice. With it, we uncovered cross-frequency-coupled theta- and gamma-range oscillations and characterized excitatory-inhibitory neural dynamics during hippocampal ripples and visual cortical processing. The TEMPO mesoscope images voltage activity in two cell-classes across a ~8-mm-wide field-of-view in head-fixed animals. In awake mice, it revealed sensory-evoked excitatory-inhibitory neural interactions and traveling gamma and 3-7 Hz waves in the visual cortex, and previously unreported propagation directions for hippocampal theta and beta waves. These technologies have widespread applications probing diverse oscillations and neuron-type interactions in healthy and diseased brains.

Development of spontaneous recurrent seizures accompanied with increased rates of interictal spikes and decreased hippocampal delta and theta activities following extended kindling in mice

Interictal epileptiform discharges refer to aberrant brain electrographic signals between seizures and feature intermittent interictal spikes (ISs), sharp waves, and/or abnormal rhythms. Recognition of these epileptiform activities by electroencephalographic (EEG) examinations greatly aids epilepsy diagnosis and localization of the seizure onset zone. ISs are a major form of interictal epileptiform discharges recognized in animal models of epilepsy. Progressive changes in IS waveforms, IS rates, and/or associated fast ripple oscillations have been shown to precede the development of spontaneous recurrent seizures (SRS) in various animal models. IS expressions in the kindling model of epilepsy have been demonstrated but IS changes during the course of SRS development in extended kindled animals remain to be detailed. We hence addressed this issue using a mouse model of kindling-induced SRS. Adult C57 black mice received twice daily hippocampal stimulations until SRS occurrence, with 24-h EEG monitoring performed following 50, 80, and ≥ 100 stimulations and after observation of SRS. In the stimulated hippocampus, increases in spontaneous ISs rates, but not in IS waveforms nor IS-associated fast ripples, along with decreased frequencies of hippocampal delta and theta rhythms, were observed before SRS onset. Comparable increases in IS rates were further observed in the unstimulated hippocampus, piriform cortex, and entorhinal cortex, but not in the unstimulated parietal cortex and dorsomedial thalamus. These data provide original evidence suggesting that increases in hippocampal IS rates, together with reductions in hippocampal delta and theta rhythms are closely associated with development of SRS in a rodent kindling model.

Border cells without theta rhythmicity in the medial prefrontal cortex

The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one’s current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.

Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity

Objective. Therapeutic brain stimulation is conventionally delivered using constant-frequency stimulation pulses. Several recent clinical studies have explored how unconventional and irregular temporal stimulation patterns could enable better therapy. However, it is challenging to understand which irregular patterns are most effective for different therapeutic applications given the massively high-dimensional parameter space. Approach. Here we applied many irregular stimulation patterns in a single neural circuit to demonstrate how they can enable new dimensions of neural control compared to conventional stimulation, to guide future exploration of novel stimulation patterns in translational settings. We optogenetically excited the septohippocampal circuit with constant-frequency, nested pulse, sinusoidal, and randomized stimulation waveforms, systematically varying their amplitude and frequency parameters. Main results. We first found equal entrainment of hippocampal oscillations: all waveforms provided similar gamma-power increase, whereas no parameters increased theta-band power above baseline (despite the mechanistic role of the medial septum in driving hippocampal theta oscillations). We then compared each of the effects of each waveform on high-dimensional multi-band activity states using dimensionality reduction methods. Strikingly, we found that conventional stimulation drove predominantly ‘artificial’ (different from behavioral activity) effects, whereas all irregular waveforms induced activity patterns that more closely resembled behavioral activity. Significance. Our findings suggest that irregular stimulation patterns are not useful when the desired mechanism is to suppress or enhance a single frequency band. However, novel stimulation patterns may provide the greatest benefit for neural control applications where entraining a particular mixture of bands (e.g. if they are associated with different symptoms) or behaviorally-relevant activity is desired.

Serotonin modulates infraslow oscillation in the dentate gyrus during Non-REM sleep.

Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with electrophysiological and optical imaging tools during sleep-wake cycles. We found that the activity of major glutamatergic cell populations in the DG is organized into in-fraslow oscillations (0.01 - 0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep. Further experiments revealed that the infraslow oscillation in the DG is modulated by rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by 5-HT1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.

Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Exploration of the Propagation of Hippocampal Theta Oscillations in Freely Moving Rats

Comprehending the mechanisms by which theta waves propagate across the hippocampus is of utmost importance in understanding various aspects of cognition in rodent models. A popular argument made by those studying hippocampal rhythms is that they are synchronous throughout the medial temporal lobe. However, recent studies have concluded that theta oscillations travel as waves along the septotemporal axis of the hippocampus. Our experimental goal was to derive a relationship between theta oscillations in the anterior and posterior regions of the hippocampus by examining local field potential in freely moving rats. We trained a mixed-sex cohort of five Fisher Brown Norway hybrid rats to run on a circular track for a food reward and implanted them with an intracranial silicon probe in the CA1 region of the anterior dorsal hippocampus (AP: -2.8 ML: 1.5 DV: 4.0) and the CA1 region of the posterior parietal hippocampus (AP: -5.6 ML: 4.2 DV: 4.5). After a recovery period, the rats were reintroduced to the circular track where data was collected from each site. This poster presents the activity of traveling dentate spikes, ripples, theta, and gamma within these hippocampal regions. R01MH126236 1R01MH109548-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Paradoxical boosting of weak and strong spatial memories by hippocampal dopamine uncaging.

The ability to remember changes in the surroundings is fundamental for daily life. It has been proposed that novel events producing dopamine release in the hippocampal CA1 region could modulate spatial memory formation. However, the role of hippocampal dopamine increase on weak or strong spatial memories remains unclear. We show that male mice exploring two objects located in a familiar environment for 5 minutes created a short-term memory (weak) that cannot be retrieved one day later, whereas 10 minutes exploration created a long-term memory (strong) that can be retrieved one day later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval one day later but dopamine elevation during the encoding of strong OLMs promoted the preference for a familiar object location over a novel object location after 24 hours. Moreover, dopamine uncaging after the encoding of OLMs did not have effect on weak memories whereas on strong memories diminished the exploration of the novel object location. Additionally, hippocampal dopamine elevation during the retrieval of OLMs did not allow the recovery of weak memories and did not affect the retrieval of strong memory traces. Finally, dopamine elevation increased hippocampal theta oscillations, indicating that dopamine promotes the recurrent activation of specific groups of neurons. Our experiments demonstrate that hippocampal dopaminergic modulation during the encoding of OLMs depends on memory strength indicating that hyperdopaminergic levels that enhance weak experiences could compromise the normal storage of strong memories.Significance statement Increased levels of dopamine have been related to cognitive enhancement. Hippocampal dopamine elevation caused by novelty exposure has been proposed as a strategy to enhance memory based on the observation that surprising events create flashbulb memories that are remembered for long time. However, hyperdopaminergic levels could also underlie maladaptive memories, such as non-desired preservation of traumatic experiences. Our experiments show that dopamine elevation in the dorsal hippocampus during the encoding of spatial memories has paradoxical effects, while the enhancement of weak memories allows their retrieval, the dopaminergic modulation of strong memories limits the ability to modify preexisting spatial memories by changes in the environment. We conclude that cognitive enhancement through dopamine boosting must consider diverse aspects of memory formation.

Optogenetic stimulation of medial septal glutamatergic neurons modulates theta-gamma coupling in the hippocampus

Hippocampal cross-frequency theta-gamma coupling (TGC) is a basic mechanism for information processing, retrieval, and consolidation of long-term and working memory. While the role of entorhinal afferents in the modulation of hippocampal TGC is widely accepted, the influence of other main input to the hippocampus, from the medial septal area (MSA, the pacemaker of the hippocampal theta rhythm) is poorly understood. Optogenetics allows us to explore how different neuronal populations of septohippocampal circuits control neuronal oscillations in vivo. Rhythmic activation of septal glutamatergic neurons has been shown to drive hippocampal theta oscillations, but the role of these neuronal populations in information processing during theta activation has remained unclear. Here we investigated the influence of phasic activation of MSA glutamatergic neurons expressing channelrhodopsin II on theta-gamma coupling in the hippocampus. During the experiment, local field potentials of MSA and hippocampus of freely behaving mice were modulated by 470 nm light flashes with theta frequency (2–10) Hz. It was shown that both the power and the strength of modulation of gamma rhythm nested on hippocampal theta waves depend on the frequency of stimulation. The modulation of the amplitude of slow gamma rhythm (30–50 Hz) prevailed over modulation of fast gamma (55–100 Hz) during flash trains and the observed effects were specific for theta stimulation of MSA. We discuss the possibility that phasic depolarization of septal glutamatergic neurons controls theta-gamma coupling in the hippocampus and plays a role in memory retrieval and consolidation.

Modulation of hippocampal theta oscillations via deep brain stimulation of the parietal cortex depends on cognitive state

The angular gyrus (AG) and posterior cingulate cortex (PCC) demonstrate extensive structural and functional connectivity with the hippocampus and other core recollection network regions. Consequently, recent studies have explored neuromodulation targeting these and other regions as a potential strategy for restoring function in memory disorders such as Alzheimer's Disease. However, determining the optimal approach for neuromodulatory devices requires understanding how parameters like selected stimulation site, cognitive state during modulation, and stimulation duration influence the effects of deep brain stimulation (DBS) on electrophysiological features relevant to episodic memory. We report experimental data examining the effects of high-frequency stimulation delivered to the AG or PCC on hippocampal theta oscillations during the memory encoding (study) or retrieval (test) phases of an episodic memory task. Results showed selective enhancement of anterior hippocampal slow theta oscillations with stimulation of the AG preferentially during memory retrieval. Conversely, stimulation of the PCC attenuated slow theta oscillations. We did not observe significant behavioral effects in this (open-loop) stimulation experiment, suggesting that neuromodulation strategies targeting episodic memory performance may require more temporally precise stimulation approaches.

Preoperative recovery sleep ameliorates postoperative cognitive dysfunction aggravated by sleep fragmentation in aged mice by enhancing EEG delta-wave activity and LFP theta oscillation in hippocampal CA1

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus.

147 Medial Septal Nucleus Theta Stimulation Improves Spatial Working Memory and Increases Hippocampal Neurovascular Activity in a Mouse Model of Alzheimers Disease (5xFAD)

INTRODUCTION: Alzheimer’s disease (AD) remains among the most prolific neurodegenerative disorders. The pathogenesis is the result, in part, of aberrant cerebral circuitry; in particular, the mesolimbic-septohippocampal circuit and its associated medial septal nucleus (MSN). Interestingly, the administration of theta stimulation via deep brain stimulation (DBS) to the MSN has been demonstrated to increase hippocampal theta oscillations, which are critical to the role of the hippocampus in learning and memory. Recently, functional ultrasound imaging (fUSI) has emerged as a method of evaluating large-scale neural activity with both high spatiotemporal resolution (∼100 μm3) and sensitivity to slow blood flow (∼1 mm/s). fUSI allows for the in-vivo analyses of neurovascular changes secondary to our theta-burst neuromodulatory intervention. METHODS: 12 male 5xFAD mice were partitioned into two groups, one received theta-burst stimulation targeting the MSN (n = 4) and the other acted as controls (n = 8). Following stimulation, spatial working memory was assessed via the Barnes maze task. An additional 44 C57BL/6 mice were partitioned into three groups: one receiving theta (7.7 Hz) stimulation to the MSN (n = 16), one receiving gamma stimulation to the MSN (100 Hz, n = 14), and the remaining group acting as the control (n = 14). RESULTS: The MSN theta stimulation group of 5xFAD mice demonstrated decreased latency compared to controls (p = 0.003). CBF volumes in the hippocampus were relatively increased in the theta-burst group when compared to both control and gamma stimulation groups. CONCLUSIONS: Our results demonstrate significant improvement in cognitive performance secondary to MSN theta-burst stimulation. Additionally, these changes were mirrored by CBF volume increases in the hippocampus in a frequency-dependent manner. These findings provide evidence for the therapeutic role of theta MSN stimulation in the treatment of AD and furthers fUSI’s role in evaluating in-vivo CBF.