Beyond hippocampus: Thalamic and prefrontal contributions to an evolving memory.

The hippocampus has long been at the center of memory research, and rightfully so. However, with emerging technological capabilities, we can increasingly appreciate memory as a more dynamic and brain-wide process. In this perspective, our goal is to begin developing models to understand the gradual evolution, reorganization, and stabilization of memories across the brain after their initial formation in the hippocampus. By synthesizing studies across the rodent and human literature, we suggest that as memory representations initially form in hippocampus, parallel traces emerge in frontal cortex that cue memory recall, and as they mature, with sustained support initially from limbic then diencephalic then cortical circuits, they become progressively independent of hippocampus and dependent on a mature cortical representation. A key feature of this model is that, as time progresses, memory representations are passed on to distinct circuits with progressively longer time constants, providing the opportunity to filter, forget, update, or reorganize memories in the process of committing to long-term storage.

Neural activity ramps in frontal cortex signal extended motivation during learning.

Learning requires the ability to link actions to outcomes. How motivation facilitates learning is not well understood. We designed a behavioral task in which mice self-initiate trials to learn cue-reward contingencies and found that the anterior cingulate region of the prefrontal cortex (ACC) contains motivation-related signals to maximize rewards. In particular, we found that ACC neural activity was consistently tied to trial initiations where mice seek to leave unrewarded cues to reach reward-associated cues. Notably, this neural signal persisted over consecutive unrewarded cues until reward associated cues were reached, and was required for learning. To determine how ACC inherits this motivational signal we performed projection specific photometry recordings from several inputs to ACC during learning. In doing so, we identified a ramp in bulk neural activity in orbitofrontal cortex (OFC) -to-ACC projections as mice received unrewarded cues, which continued ramping across consecutive unrewarded cues, and finally peaked upon reaching a reward associated cue, thus maintaining an extended motivational state. Cellular resolution imaging of OFC confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to convey an extended motivational state to ACC to facilitate goal-directed learning.

Anteromedial thalamus gates the selection and stabilization of long-term memories.

Memories initially formed in hippocampus gradually stabilize to cortex over weeks-to-months for long-term storage. The mechanistic details of this brain re-organization remain poorly understood. We recorded bulk neural activity in circuits that link hippocampus and cortex as mice performed a memory-guided virtual-reality task over weeks. We identified a prominent and sustained neural correlate of memory in anterior thalamus, whose inhibition substantially disrupted memory consolidation. More strikingly, gain amplification enhanced consolidation of otherwise unconsolidated memories. To gain mechanistic insights, we developed a technology for simultaneous cellular-resolution imaging of hippocampus, thalamus, and cortex throughout consolidation. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus preferentially encodes salient memories, and gradually increases correlations with cortex to facilitate tuning and synchronization of cortical ensembles. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer-term cortical storage.

Anteromedial Thalamus Gates the Selection & Stabilization of Long-Term Memories.

Memories initially formed in hippocampus gradually stabilize to cortex, over weeks-to-months, for long-term storage. The mechanistic details of this brain re-organization process remain poorly understood. In this study, we developed a virtual-reality based behavioral task and observed neural activity patterns associated with memory reorganization and stabilization over weeks-long timescales. Initial photometry recordings in circuits that link hippocampus and cortex revealed a unique and prominent neural correlate of memory in anterior thalamus that emerged in training and persisted for several weeks. Inhibition of the anteromedial thalamus-to-anterior cingulate cortex projections during training resulted in substantial memory consolidation deficits, and gain amplification more strikingly, was sufficient to enhance consolidation of otherwise unconsolidated memories. To provide mechanistic insights, we developed a new behavioral task where mice form two memories, of which only the more salient memory is consolidated, and also a technology for simultaneous and longitudinal cellular resolution imaging of hippocampus, thalamus, and cortex throughout the consolidation window. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus forms preferential tuning to salient memories, and establishes inter-regional correlations with cortex, that are critical for synchronizing and stabilizing cortical representations at remote time. Indeed, inhibition of this thalamo-cortical circuit while imaging in cortex reveals loss of contextual tuning and ensemble synchrony in anterior cingulate, together with behavioral deficits in remote memory retrieval. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer term cortical storage.

Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An in vivo multiphoton microscopy evaluation.

Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO2), behavioral outcomes, and neuropathology in 16-18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1-3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30-60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.

Optimizing Hippocampal-Cortical Network Modulation via Repetitive Transcranial Magnetic Stimulation: A Dose-Finding Study Using the Continual Reassessment Method.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) can cause potentially useful changes in brain functional connectivity (FC), but the number of treatment sessions required is unknown. We applied the continual reassessment method (CRM), a Bayesian, adaptive, dose-finding procedure to a rTMS paradigm in an attempt to answer this question. MATERIALS AND METHODS: The sample size was predetermined at 15 subjects and the cohort size was set with three individuals (i.e., five total cohorts). In a series of consecutive daily sessions, we delivered rTMS to the left posterior parietal cortex and measured resting-state FC with fMRI in a predefined hippocampal network in the left hemisphere. The session number for each successive cohort was determined by the CRM algorithm. We set a response criterion of a 0.028 change in FC between the hippocampus and the parietal cortex, which was equal to the increase seen in 87.5% of participants in a previous study using five sessions. RESULTS: A ≥criterion change was observed in 9 of 15 participants. The CRM indicated that greater than four sessions are required to produce the criterion change reliably in future studies. CONCLUSIONS: The CRM can be adapted for rTMS dose finding when a reliable outcome measure, such as FC, is available. The minimum effective dose needed to produce a criterion increase in FC in our hippocampal network of interest at 87.5% efficacy was estimated to be greater than four sessions. This study is the first demonstration of a Bayesian, adaptive method to explore a rTMS parameter.

Competitive and cooperative interactions between medial temporal and striatal learning systems.

The striatum and medial temporal lobes (MTL) exhibit dissociable roles during learning. Whereas the striatum and its network of thalamic relays and cortical nodes are necessary for nondeclarative learning, the MTL and associated network are required for declarative learning. Several studies have suggested that these networks are functionally competitive during learning. Since these discoveries, however, evidence has accumulated that they can operate in a cooperative fashion. In this review, we discuss evidence for both competition and cooperation between these systems during learning, with the aim of reconciling these seemingly contradictory findings. Examples of cooperation between the striatum and MTL have been provided, especially during consolidation and generalization of knowledge, and do not appear to be precluded by differences in functional specialization. However, whether these systems cooperate or compete does seem to depend on the phase of learning and cognitive or motor aspects of the task. The involvement of other regions, such as midbrain dopaminergic nuclei and the prefrontal cortex, may promote and mediate cooperation between the striatum and the MTL during learning. Building on this body of research, we propose a model for striatum-MTL interactions in learning and memory and attempt to predict, in general terms, when cooperation or competition will occur.

Persistent Enhancement of Hippocampal Network Connectivity by Parietal rTMS Is Reproducible.

Wang et al. (2014) found that that five daily sessions of repetitive transcranial magnetic stimulation (rTMS) of the posterior parietal cortex (PPC) significantly increased functional connectivity (FC) in a network centered on the hippocampus, and caused a correlated increase in memory performance. However, this finding has not been reproduced independently and the requirement for five sessions has not been validated. We aimed to reproduce the imaging results of this experiment, focusing on hippocampal FC changes and using fewer days of rTMS. We measured resting state FC before and after three (N = 9) or four (N = 6) consecutive daily PPC rTMS sessions, using similar delivery parameter settings as Wang et al. (2014) Eight subjects received 3 d of rTMS delivered to the vertex as a control. We employed whole-brain and hypothesis-based statistical approaches to test for hippocampal FC changes. Additionally, we calculated FC in 17 brain networks to determine whether the topographic pattern of FC change was similar between studies. We did not include behavioral testing in this study. PPC, but not vertex, rTMS caused significant changes in hippocampal FC to the same regions as in the previous study. Brain-wide changes in hippocampal FC significantly exceeded changes in global connectedness, indicating that the effect of PPC rTMS was specific to the hippocampal network. Baseline hippocampal FC, measured before receiving stimulation, predicted the degree of rTMS-induced hippocampal FC as in the previous study. These findings reproduce the imaging findings of Wang et al. (2014) and show that FC enhancement can occur after only three to four sessions of PPC rTMS.

Probabilistic inferential decision-making under time pressure in rhesus macaques (Macaca mulatta).

Decisions often involve the consideration of multiple cues, each of which may inform selection on the basis of learned probabilities. Our ability to use probabilistic inference for decisions is bounded by uncertainty and constraints such as time pressure. Previous work showed that when humans choose between visual objects in a multiple-cue, probabilistic task, they cope with time pressure by discounting the least informative cues, an example of satisficing or "good enough" decision-making. We tested two rhesus macaques (Macaca mulatta) on a similar task to assess their capacity for probabilistic inference and satisficing in comparison with humans. In each trial, a monkey viewed two compound stimuli consisting of four cue dimensions. Each dimension (e.g., color) had two possible states (e.g., red or blue) with different probabilistic weights. Selecting the stimulus with highest total weight yielded higher odds of receiving reward. Both monkeys learned the assigned weights at high accuracy. Under time pressure, both monkeys were less accurate as a result of decreased use of cue information. One monkey adopted the same satisficing strategy used by humans, ignoring the least informative cue dimension. Both monkeys, however, exhibited a strategy not reported for humans, a "group-the-best" strategy in which the top two cues were used similarly despite their different assigned weights. The results validate macaques as an animal model of probabilistic decision-making, establishing their capacity to discriminate between objects using at least four visual dimensions simultaneously. The time pressure data suggest caution, however, in using macaques as models of human satisficing. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

An automated rat single pellet reaching system with high-speed video capture.

BACKGROUND: Single pellet reaching is an established task for studying fine motor control in which rats reach for, grasp, and eat food pellets in a stereotyped sequence. Most incarnations of this task require constant attention, limiting the number of animals that can be tested and the number of trials per session. Automated versions allow more interventions in more animals, but must be robust and reproducible. NEW METHOD: Our system automatically delivers single reward pellets for rats to grasp with their forepaw. Reaches are detected using real-time computer vision, which triggers video acquisition from multiple angles using mirrors. This allows us to record high-speed (>300 frames per second) video, and trigger interventions (e.g., optogenetics) with high temporal precision. Individual video frames are triggered by digital pulses that can be synchronized with behavior, experimental interventions, or recording devices (e.g., electrophysiology). The system is housed within a soundproof chamber with integrated lighting and ventilation, allowing multiple skilled reaching systems in one room. RESULTS: We show that rats acquire the automated task similarly to manual versions, that the task is robust, and can be synchronized with optogenetic interventions. COMPARISON WITH EXISTING METHODS: Existing skilled reaching protocols require high levels of investigator involvement, or, if ad libitum, do not allow for integration of high-speed, synchronized data collection. CONCLUSION: This task will facilitate the study of motor learning and control by efficiently recording large numbers of skilled movements. It can be adapted for use with modern neurophysiology, which demands high temporal precision.