Episodic memory requires the hippocampus, which is thought to bind cortical inputs into conjunctive codes. Local field potentials (LFPs) reflect dendritic and synaptic oscillations whose temporal structure may coordinate cellular mechanisms of plasticity and memory. We now report that single-trial spatial memory performance in rats was predicted by the power comodulation of theta (4-10 Hz) and low gamma (30-50 Hz) rhythms in the hippocampus. Theta-gamma comodulation (TGC) was prominent during successful memory retrieval but was weak when memory failed or was unavailable during spatial exploration in sample trials. Muscimol infusion into medial septum reduced the probability of TGC and successful memory retrieval. In contrast, patterned electrical stimulation of the fimbria-fornix increased TGC in amnestic animals and partially rescued memory performance in the water maze. The results suggest that TGC accompanies memory retrieval in the hippocampus and that patterned brain stimulation may inform therapeutic strategies for cognitive disorders.hippocampus | medial septum | theta-burst stimulation | fimbria-fornix | retrieval E pisodic memory stores the spatial, temporal, and personal contexts of events and requires the brain to represent temporally extended, sequential information (1). Cross-frequency power comodulation (2), defined as correlated spectral power fluctuations between different frequency waves (3), may provide a mechanism for coding episodic sequences by coordinating neuronal activity in timescales required for synaptic plasticity, memory encoding, and retrieval (4-6). A prominent theory suggests that ordered items in memory are coded by subdividing each hippocampal theta cycle (4-10 Hz) with multiple cortical gamma cycles . This temporal formatting may organize episodic sequences as coordinated firing of multiple cell assemblies (7-9). The theta-gamma discrete phase code hypothesis has been implemented in computational models (7), and neocortical thetagamma phase-amplitude correlation is observed in waking rats (10), accompanies working memory in humans (11), and recently has been linked to learning item-context associations in rats (12). Although phase-amplitude relations have been studied, less is known about correlations between theta and gamma power in the processes of memory acquisition and retrieval. Correlated theta and gamma power may be necessary for hippocampus-dependent memory, but this prediction has not been tested directly.Hippocampal theta and gamma oscillations have been associated independently with memory performance in many tasks. Theta rhythm correlates positively with learning in classical conditioning (13) and human episodic memory tasks (14, 15). Medial septal (MS) lesions reduce hippocampal theta rhythm and impair spatial memory in rats (16), as do infusions of muscimol (a GABA A agonist) into the MS (17, 18). Memory retrieval also has been associated with transient gamma oscillations in CA1 and CA3 (19). In particular, low gamma (30-50 Hz) activity may help couple CA3 and CA1...

Central thalamic electrical stimulation has been proposed as a method for remediation of acquired cognitive disability. Longstanding experimental and clinical observations indicate a key role for neurons within the central thalamus in maintaining the alert waking state and facilitating attended behaviors. Here, we show that continuous high frequency (100 Hz) electrical stimulation of the central thalamus generates widespread cortical activation of c-fos across all cortical layers and a selective pattern of regulation of zif268 within the supragranular, granular, and infragranular cortical laminae. Significant elevation of both immediate early genes also is seen in the dentate gyrus of the hippocampus. Use of the same stimulation parameters is shown to facilitate untrained goal-directed seeking behavior and object recognition memory in rodents. An overall increase of exploratory motor behaviors and grooming activity also is observed, consistent with a global increase in arousal. Taken together, these studies indicate that electrical stimulation of the central thalamus may enhance cognitive performance through neocortical and hippocampal neuronal activation and specific regulation of gene expression.attention ͉ deep brain stimulation ͉ gene expression ͉ intralaminar thalamus ͉ neuromodulation E lectrical stimulation of brainstem, thalamic, and basal ganglia structures is a rapidly emerging therapeutic technique for neuropsychiatric disorders, but knowledge of underlying mechanisms is limited (1, 2). Central thalamic stimulation has been proposed for the treatment of impaired cognitive function (3). Neurons within the intralaminar nuclei and paralaminar regions of the central thalamus link brainstem arousal systems to cerebral cortical and basal ganglia networks crucial to the organization of wakeful behaviors (4-8). To investigate the impact of central thalamic electrical stimulation on cognitive function, we characterize gene expression and behavioral effects of electrical stimulation centered on the central lateral (CL) nucleus of the rat anterior intralaminar thalamic nuclei (part of the central thalamus). We hypothesize that electrical stimulation of CL and surrounding regions may increase vigilance and cognitive performance in the intact animal. We assess functional activation associated with CL stimulation by using patterns of immediate-early gene expression in cortical and subcortical structures. Electrical stimulation of CL produced ipsilateral up-regulation of c-fos and zif268 expression with laminar specificity in the motor cortex (mCtx), anterior cingulate cortex (ACC), caudate-putamen (CP), and bilateral elevation in hippocampi at 2 hours after stimulation. In a separate series of experiments, unilateral high-frequency (100 Hz) electrical stimulation of CL in awake animals produced significant improvements in performance and learning of a visual object recognition task compared with control animals. These findings indicate that in vivo stimulation of central thalamus targeting CL activates a wide cereb...

Neurons in the rat hippocampus signal current location by firing in restricted areas called place fields. During goal-directed tasks in mazes, place fields can also encode past and future positions through journey-dependent activity, which could guide hippocampus-dependent behavior and underlie other temporally extended memories, such as autobiographical recollections. The relevance of journey-dependent activity for hippocampal-dependent memory, however, is not well understood. To further investigate the relationship between hippocampal journey-dependent activity and memory we compared neural firing in rats performing two mnemonically distinct but behaviorally identical tasks in the plus maze: a hippocampus-dependent spatial navigation task, and a hippocampus-independent cue response task. While place, prospective, and retrospective coding reflected temporally extended behavioral episodes in both tasks, memory strategy altered coding differently before and after the choice point. Before the choice point, when discriminative selection of memory strategy was critical, a switch between the tasks elicited a change in a field’s coding category, so that a field that signaled current location in one task coded pending journeys in the other task. After the choice point, however, when memory strategy became irrelevant, the fields preserved coding categories across tasks, so that the same field consistently signaled either current location or the recent journeys. Additionally, on the start arm firing rates were affected at comparable levels by task and journey, while on the goal arm firing rates predominantly encoded journey. The data demonstrate a direct link between journey-dependent coding and memory, and suggest that episodes are encoded by both population and firing rate coding.

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Memory influences learning, but how neural signals support such transfer are unknown. To investigate these mechanisms, we trained rats to perform a standard spatial memory task in a plus maze and tested how training affected learning and neural coding in two new task variants. A switch task exchanged the start and goal locations in the same environment; whereas an altered environment task contained different local and distal cues. Learning was facilitated in both variants compared to the acquisition of the standard task. In the switch task, performance was largely maintained, and was accompanied by immediate and stable place field remapping. Place field maps in CA1 were anticorrelated in the standard and switch sessions, and the anti-correlation co-varied with switch performance. Simultaneously, CA3 maps were uncorrelated overall in the standard and switch, though many CA3 cells had fields in shifted locations in the same maze arms. In the altered environment task, performance was initially impaired, and place fields changed dynamically. CA1 fields were initially unstable, and their stabilization correlated with improving performance. Most CA3 cells, however, stopped firing on the maze in the altered environment, even as the same cells maintained prominent fields in standard sessions recorded before and after. CA1 and CA3 place fields thus revealed different coding dynamics that correlated with both learning and memory performance. Together, CA1 and CA3 ensembles represented the similarities and differences between new and familiar situations through concurrent rate and place remapping.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer’s disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.

Pain is a subjective experience that alerts an individual to actual or potential tissue damage. Through mechanisms that are still unclear, normal physiological pain can lose its adaptive value and evolve into pathological chronic neuropathic pain. Chronic pain is a multifaceted experience that can be understood in terms of somatosensory, affective, and cognitive dimensions, each with associated symptoms and neural signals. While there have been many attempts to treat chronic pain, in this article we will argue that feedback-controlled ‘closed-loop’ deep brain stimulation (DBS) offers an urgent and promising route for treatment. Contemporary DBS trials for chronic pain use “open-loop” approaches in which tonic stimulation is delivered with fixed parameters to a single brain region. The impact of key variables such as the target brain region and the stimulation waveform is unclear, and long-term efficacy has mixed results. We hypothesize that chronic pain is due to abnormal synchronization between brain networks encoding the somatosensory, affective and cognitive dimensions of pain, and that multisite, closed-loop DBS provides an intuitive mechanism for disrupting that synchrony. By (1) identifying biomarkers of the subjective pain experience and (2) integrating these signals into a state-space representation of pain, we can create a predictive model of each patient's pain experience. Then, by establishing how stimulation in different brain regions influences individual neural signals, we can design real-time, closed-loop therapies tailored to each patient. While chronic pain is a complex disorder that has eluded modern therapies, rich historical data and state-of-the-art technology can now be used to develop a promising treatment.

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