Goal Choices Modify Frontotemporal Memory Representations.

Adapting flexibly to changing circumstances is guided by memory of past choices, their outcomes in similar circumstances, and a method for choosing among potential actions. The hippocampus (HPC) is needed to remember episodes, and the prefrontal cortex (PFC) helps guide memory retrieval. Single-unit activity in the HPC and PFC correlates with such cognitive functions. Previous work recorded CA1 and mPFC activity as male rats performed a spatial reversal task in a plus maze that requires both structures, found that PFC activity helps reactivate HPC representations of pending goal choices but did not describe frontotemporal interactions after choices. We describe these interactions after choices here. CA1 activity tracked both current goal location and the past starting location of single trials; PFC activity tracked current goal location better than past start location. CA1 and PFC reciprocally modulated representations of each other both before and after goal choices. After choices, CA1 activity predicted changes in PFC activity in subsequent trials, and the magnitude of this prediction correlated with faster learning. In contrast, PFC start arm activity more strongly modulated CA1 activity after choices correlated with slower learning. Together, the results suggest post-choice HPC activity conveys retrospective signals to the PFC, which combines different paths to common goals into rules. In subsequent trials, prechoice mPFC activity modulates prospective CA1 signals informing goal selection.SIGNIFICANCE STATEMENT HPC and PFC activity supports cognitive flexibility in changing circumstances. HPC signals represent behavioral episodes that link the start, choice, and goal of paths. PFC signals represent rules that guide goal-directed actions. Although prior studies described HPC-PFC interactions preceding decisions in the plus maze, post-decision interactions were not investigated. Here, we show post-choice HPC and PFC activity distinguished the start and goal of paths, and CA1 signaled the past start of each trial more accurately than mPFC. Postchoice CA1 activity modulated subsequent PFC activity, so rewarded actions were more likely to occur. Together, the results show that in changing circumstances, HPC retrospective codes modulate subsequent PFC coding, which in turn modulates HPC prospective codes that predict choices.

Prehospital Naloxone Administration Patterns during the Era of Synthetic Opioids.

Background: The opioid epidemic is an ongoing public health emergency, exacerbated in recent years by the introduction and rising prevalence of synthetic opioids. The National EMS Scope of Practice Model was changed in 2017 to recommend allowing basic life support (BLS) clinicians to administer intranasal (IN) naloxone. This study examines local IN naloxone administration rates for 4 years after the new recommendation, and Glasgow Coma Scale (GCS) scores and respiratory rates before and after naloxone administration.Methods: This retrospective cohort study evaluated naloxone administrations between April 1st 2017 and March 31st 2021 in a mixed urban-suburban EMS system. Naloxone dosages, routes of administration, and frequency of administrations were captured along with demographic information. Analysis of change in the ratio of IN to intravenous (IV) naloxone administrations per patient was performed, with the intention of capturing administration patterns in the area. Analyses were performed for change over time of IN naloxone rates of administration, change in respiratory rates, and change in GCS scores after antidote administration. ALS and BLS clinician certification levels were also identified. Bootstrapping procedures were used to estimate 95% confidence intervals for correlation coefficients.Results: Two thousand and ninety patients were analyzed. There was no statistically significant change in the IN/parenteral ratio over time (p = 0.79). Repeat dosing increased over time from 1.2 ± 0.4 administrations per patient to 1.3 ± 0.5 administrations per patient (r = 0.078, 95% CI: 0.036 - 0.120; p = 0.036). Mean respiratory rates before (mean = 12.6 - 12.6, r = -0.04, 95% CI: -0.09 - 0.01; p = 0.1) and after (mean = 15.2 - 14.9, r = -0.03, 95% CI: -0.08 - 0.01; p = 0.172) naloxone administration have not changed. While initial GCS scores have become significantly lower, GCS scores after administration of naloxone have not changed (initial median GCS 10 - 6, p < 0.001; final median GCS 15 - 15, p = 0.23).Conclusions: Current dosing protocols of naloxone appear effective in the era of synthetic opioids in our region, although patients may be marginally more likely to require repeat naloxone doses.

EMS Non-Transport of Low-Risk COVID-19 Patients.

Objectives: COVID-19 infections in the community have the potential to overwhelm both prehospital and in-hospital resources. Transport of well-appearing patients, in the absence of available emergency department treatment capacity, increases strain on the hospital and EMS system. In May of 2020, the Connecticut Office of EMS issued a voluntary, EMS-initiated, non-transport protocol for selected low-risk patients with symptoms consistent with COVID-19. We evaluated the implementation of this non-transport protocol in a mixed urban/suburban EMS system.Methods: We conducted a retrospective review of contemporaneously recorded quality improvement documentation for uses of the Connecticut COVID-19 non-transport protocol by EMS clinicians within our EMS system during two implementations: from 12/14/2020 to 5/1/21, and again from 1/3/22 to 2/18/22, which coincided with large COVID-19 case surges in our region.Results: The vast majority of patients treated under the non-transport protocol were not reevaluated by EMS or in our emergency departments in the subsequent 24 hours. There was reasonable adherence to the protocol, with 83% of cases appropriate for the non-transport protocol. The most common reasons for protocol violations were age outside of protocol scope (pediatric patients), failure of documentation, or vital signs outside of the established protocol parameters. We did not find an increased 24-hour ED visit rate in patients who were inappropriately triaged to the protocol. Of patients who had ED visits within 24 hours, only two were admitted, none to higher levels of care.Conclusion: Within this small study, EMS clinicians in our system were able to safely and accurately apply a non-transport protocol for patients presenting with symptoms consistent with COVID-19. This is consistent with previous literature suggesting that EMS-initiated non-transport is a viable strategy to reduce the burden on health systems.

An Evaluation of Prehospital Adenosine Use.

BACKGROUND: Adenosine has been safely used by paramedics for the treatment of stable supraventricular tachycardia since the mid-1990s. However, there continues to be variability in paramedics' ability to identify appropriate indications for adenosine administration. As the first of a planned series of studies aimed at improving the accuracy of SVT diagnosis and successful administration of adenosine by paramedics, this study details the current usage patterns of adenosine by paramedics. METHODS: This cross-sectional retrospective study investigated adenosine use within a large northeast EMS region from January 1, 2019, through September 30, 2021. Excluding pediatric and duplicate case reports, we created a dataset containing patient age, sex, and vital signs before, during, and after adenosine administration; intravenous line location; and coded medical history from paramedic narrative documentation, including a history of atrial fibrillation, suspected arrhythmia diagnosis, and effect of adenosine. In cases with available prehospital electrocardiograms (EKGs) for review, two physicians independently coded the arrhythmia diagnosis and outcome of adenosine administration. Statistical analysis included interrater reliability with Cohen's kappa statistic. RESULTS: One hundred eighty-three cases were included for final analysis, 84 did not have a documented EKG for review. Categorization of presenting rhythms in these cases occurred by a physician reviewing EMS narrative and documentation. Forty of these 84 cases (48%) were adjudicated as SVT likely, 32 (38%) as SVT unlikely and 12 (14%) as uncategorized due to lack of supporting documentation. Of the 99 cases with EKGs available to review, there was substantial agreement of arrhythmia diagnosis interpretation between physician reviewers (Cohen's kappa 0.77-1.0); 54 cases were adjudicated as SVT by two physician reviewers. Other identified cardiac rhythms included atrial fibrillation (16), sinus tachycardia (11), and ventricular tachycardia (2). Adenosine cardioversion occurred in 47 of the 99 cases with EKGs available for physician review (47.5%). Adenosine cardioversion was also deemed to occur in 87% (47/54) of cases when the EKG rhythm was physician adjudicated SVT. CONCLUSIONS: This study supports the use of adenosine as a prehospital treatment for SVT while highlighting the need for continued efforts to improve paramedics' identification and management of tachyarrhythmias.

Hippocampal and Medial Prefrontal Cortex Fractal Spiking Patterns Encode Episodes and Rules.

A central question in neuroscience is how the brain represents and processes information to guide behavior. The principles that organize brain computations are not fully known, and could include scale-free, or fractal patterns of neuronal activity. Scale-free brain activity may be a natural consequence of the relatively small subsets of neuronal populations that respond to task features, i.e., sparse coding. The size of the active subsets constrains the possible sequences of inter-spike intervals (ISI), and selecting from this limited set may produce firing patterns across wide-ranging timescales that form fractal spiking patterns. To investigate the extent to which fractal spiking patterns corresponded with task features, we analyzed ISIs in simultaneously recorded populations of CA1 and medial prefrontal cortical (mPFC) neurons in rats performing a spatial memory task that required both structures. CA1 and mPFC ISI sequences formed fractal patterns that predicted memory performance. CA1 pattern duration, but not length or content, varied with learning speed and memory performance whereas mPFC patterns did not. The most common CA1 and mPFC patterns corresponded with each region's cognitive function: CA1 patterns encoded behavioral episodes which linked the start, choice, and goal of paths through the maze whereas mPFC patterns encoded behavioral "rules" which guided goal selection. mPFC patterns predicted changing CA1 spike patterns only as animals learned new rules. Together, the results suggest that CA1 and mPFC population activity may predict choice outcomes by using fractal ISI patterns to compute task features.

Flexible spatial learning requires both the dorsal and ventral hippocampus and their functional interactions with the prefrontal cortex.

When faced with changing contingencies, animals can use memory to flexibly guide actions, engaging both frontal and temporal lobe brain structures. Damage to the hippocampus (HPC) impairs episodic memory, and damage to the prefrontal cortex (PFC) impairs cognitive flexibility, but the circuit mechanisms by which these areas support flexible memory processing remain unclear. The present study investigated these mechanisms by temporarily inactivating the medial PFC (mPFC), the dorsal HPC (dHPC), and the ventral HPC (vHPC), individually and in combination, as rats learned spatial discriminations and reversals in a plus maze. Bilateral inactivation of either the dHPC or vHPC profoundly impaired spatial learning and memory, whereas bilateral mPFC inactivation primarily impaired reversal versus discrimination learning. Inactivation of unilateral mPFC together with the contralateral dHPC or vHPC impaired spatial discrimination and reversal learning, whereas ipsilateral inactivation did not. Flexible spatial learning thus depends on both the dHPC and vHPC and their functional interactions with the mPFC.

The nucleus reuniens of the thalamus sits at the nexus of a hippocampus and medial prefrontal cortex circuit enabling memory and behavior.

The nucleus reuniens of the thalamus (RE) is a key component of an extensive network of hippocampal and cortical structures and is a fundamental substrate for cognition. A common misconception is that RE is a simple relay structure. Instead, a better conceptualization is that RE is a critical component of a canonical higher-order cortico-thalamo-cortical circuit that supports communication between the medial prefrontal cortex (mPFC) and the hippocampus (HC). RE dysfunction is implicated in several clinical disorders including, but not limited to Alzheimer's disease, schizophrenia, and epilepsy. Here, we review key anatomical and physiological features of the RE based primarily on studies in rodents. We present a conceptual model of RE circuitry within the mPFC-RE-HC system and speculate on the computations RE enables. We review the rapidly growing literature demonstrating that RE is critical to, and its neurons represent, aspects of behavioral tasks that place demands on memory focusing on its role in navigation, spatial working memory, the temporal organization of memory, and executive functions.

Orbitofrontal Cortex Signals Expected Outcomes with Predictive Codes When Stable Contingencies Promote the Integration of Reward History.

Memory can inform goal-directed behavior by linking current opportunities to past outcomes. The orbitofrontal cortex (OFC) may guide value-based responses by integrating the history of stimulus-reward associations into expected outcomes, representations of predicted hedonic value and quality. Alternatively, the OFC may rapidly compute flexible "online" reward predictions by associating stimuli with the latest outcome. OFC neurons develop predictive codes when rats learn to associate arbitrary stimuli with outcomes, but the extent to which predictive coding depends on most recent events and the integrated history of rewards is unclear. To investigate how reward history modulates OFC activity, we recorded OFC ensembles as rats performed spatial discriminations that differed only in the number of rewarded trials between goal reversals. The firing rate of single OFC neurons distinguished identical behaviors guided by different goals. When >20 rewarded trials separated goal switches, OFC ensembles developed stable and anticorrelated population vectors that predicted overall choice accuracy and the goal selected in single trials. When <10 rewarded trials separated goal switches, OFC population vectors decorrelated rapidly after each switch, but did not develop anticorrelated firing patterns or predict choice accuracy. The results show that, whereas OFC signals respond rapidly to contingency changes, they predict choices only when reward history is relatively stable, suggesting that consecutive rewarded episodes are needed for OFC computations that integrate reward history into expected outcomes.SIGNIFICANCE STATEMENT Adapting to changing contingencies and making decisions engages the orbitofrontal cortex (OFC). Previous work shows that OFC function can either improve or impair learning depending on reward stability, suggesting that OFC guides behavior optimally when contingencies apply consistently. The mechanisms that link reward history to OFC computations remain obscure. Here, we examined OFC unit activity as rodents performed tasks controlled by contingencies that varied reward history. When contingencies were stable, OFC neurons signaled past, present, and pending events; when contingencies were unstable, past and present coding persisted, but predictive coding diminished. The results suggest that OFC mechanisms require stable contingencies across consecutive episodes to integrate reward history, represent predicted outcomes, and inform goal-directed choices.

Normalization to Maximal Voluntary Contraction is Influenced by Subacromial Pain.

In this study, we aimed to determine if electromyography (EMG) normalization to maximal voluntary isometric contractions (MVIC) was influenced by subacromial pain in patients with subacromial impingement syndrome. Patients performed MVICs in unique testing positions for each shoulder muscle tested before and after subacromial injection of local anesthetic. In addition to collection of MVIC data, EMG data during an arm elevation task were recorded before and after injection. From a visual analog pain scale, patients had a 64% decrease in pain following the injection. Significant increases in MVICs were noted in 4 of the 7 shoulder muscles tested: anterior, middle and posterior deltoid, and lower trapezius. No significant differences were noticed for the upper trapezius, latissimus dorsi, or serratus anterior. MVIC condition (pre and post injection) had a significant influence on EMG normalization for the anterior deltoid and lower trapezius muscle. Results indicate that subacromial pain can influence shoulder muscle activity, especially for the deltoid muscles and lower trapezius. In addition, normalization to MVIC in the presence of pain can have unpredictable results. Caution should be taken when normalizing EMG data to MVIC in the presence of pain.

A limited positioning system for memory.

The 2014 Nobel Prize for Physiology or Medicine is an enormous triumph for John O'Keefe and May-Britt and Edvard Moser and an historic event for cognitive and behavioral neuroscience. Neuronal representations decoded from action potentials form a mechanistic bridge between brain and mind and demonstrate the continuity of psychology with biology and physical science. The cognitive map theory powered an ongoing, international research program inspired by Hebb (The Organization of Behavior. New York, NY: Wiley) that showed the way toward linking specific patterns of neuronal activity to high level representation and processing. The prize celebrates a path that led from fundamental, philosophical questions about psychological space to enduring, scientific facts: place, head direction, grid, and boundary fields in the hippocampus, presubiculum, entorhinal cortex, and other brain circuits provide a cellular basis for spatial behavior, learning, and memory. By awarding this prize, the Nobel committee affirmed neuroethology and comparative psychology, marked the end of a chapter in one debate about the existence of animal cognition, and recognized cognitive neurophysiology. The "inner GPS" in the brain" demonstrates "a cellular basis for higher cognitive function." Animals represent, process, and use information defined by abstract relationships among items (O'Keefe and Conway,) to guide flexible, goal-directed actions. Beyond raising the ontological status of "animal mind," the committee agreed that abstract mental representations can be investigated rigorously by recording single unit activity in the brain of behaving animals.

Behavioral flexibility and response selection are impaired after limited exposure to oxycodone.

Behavioral flexibility allows individuals to adapt to situations in which rewards and goals change. Potentially addictive drugs may impair flexible decision-making by altering brain mechanisms that compute reward expectancies, thereby facilitating maladaptive drug use. To investigate this hypothesis, we tested the effects of oxycodone exposure on rats in two complementary learning and memory tasks that engage distinct learning strategies and neural circuits. Rats were trained first in either a spatial or a body-turn discrimination on a radial maze. After initial training, rats were given oxycodone or vehicle injections in their home cages for 5 d. Reversal learning was tested 36 h after the final drug exposure. We hypothesized that if oxycodone impaired behavioral flexibility, then drug-exposed rats should learn reversals more slowly than controls. Oxycodone exposure impaired spatial reversal learning when reward contingencies changed rapidly, but not when they changed slowly. During rapid reversals, oxycodone-exposed rats required more trials to reach criterion, made more perseverative errors, and were more likely to make errors after correct responses than controls. Oxycodone impaired body-turn reversal learning in similar patterns. Limited exposure to oxycodone reduced behavioral flexibility when rats were tested in a drug-free state, suggesting that impaired decision-making is an enduring consequence of oxycodone exposure.

N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo.

N-Cadherin and ß-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, ß-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N-cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N-cadherin/ß-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function.

A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging.

Memory decline is a common feature of aging. Expression of the immediate-early gene Arc is necessary for normal long-term memory, and although experience dependent Arc transcription is reportedly reduced in the aged rat hippocampus, it has not been clear whether this effect is an invariant consequence of growing older, or a finding linked specifically to age-related memory impairment. Here we show that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. While these findings are consistent with the possibility that blunted Arc transcription contributes to cognitive aging, we also found increased basal ARC protein levels in the CA1 field of the hippocampus in aged rats with memory impairment, together with a loss of the experience dependent increase observed in young and unimpaired aged rats. Follow-up analysis revealed that increased basal translation and blunted ubiquitin mediated degradation may contribute to increased basal ARC protein levels noted in memory impaired aged rats. These findings indicate that Arc expression is regulated at multiple levels, and that several of these mechanisms are altered in cognitively impaired aged rats. Defining the influence of these alterations on the spatial and temporal fidelity of synapse specific, memory-related plasticity in the aged hippocampus is an important challenge.

Remembering to learn: independent place and journey coding mechanisms contribute to memory transfer.

The neural mechanisms that integrate new episodes with established memories are unknown. When rats explore an environment, CA1 cells fire in place fields that indicate locations. In goal-directed spatial memory tasks, some place fields differentiate behavioral histories ("journey-dependent" place fields) while others do not ("journey-independent" place fields). To investigate how these signals inform learning and memory for new and familiar episodes, we recorded CA1 and CA3 activity in rats trained to perform a "standard" spatial memory task in a plus maze and in two new task variants. A "switch" task exchanged the start and goal locations in the same environment; an "altered environment" task contained unfamiliar local and distal cues. In the switch task, performance was mildly impaired, new firing maps were stable, but the proportion and stability of journey-dependent place fields declined. In the altered environment, overall performance was strongly impaired, new firing maps were unstable, and stable proportions of journey-dependent place fields were maintained. In both tasks, memory errors were accompanied by a decline in journey codes. The different dynamics of place and journey coding suggest that they reflect separate mechanisms and contribute to distinct memory computations. Stable place fields may represent familiar relationships among environmental features that are required for consistent memory performance. Journey-dependent activity may correspond with goal-directed behavioral sequences that reflect expectancies that generalize across environments. The complementary signals could help link current events with established memories, so that familiarity with either a behavioral strategy or an environment can inform goal-directed learning.

Reward stability determines the contribution of orbitofrontal cortex to adaptive behavior.

Animals respond to changing contingencies to maximize reward. The orbitofrontal cortex (OFC) is important for flexible responding when established contingencies change, but the underlying cognitive mechanisms are debated. We tested rats with sham or OFC lesions in radial maze tasks that varied the frequency of contingency changes and measured both perseverative and non-perseverative errors. When contingencies were changed rarely, rats with sham lesions learned quickly and performed better than rats with OFC lesions. Rats with sham lesions made fewer non-perseverative errors, rarely entering non-rewarded arms, and more win-stay responses by returning to recently rewarded arms compared with rats with OFC lesions. When contingencies were changed rapidly, however, rats with sham lesions learned slower, made more non-perseverative errors and fewer lose-shift responses, and returned more often to non-rewarded arms than rats with OFC lesions. The results support the view that the OFC integrates reward history and suggest that the availability of outcome expectancy signals can either improve or impair adaptive responding depending on reward stability.

Bidirectional changes to hippocampal theta-gamma comodulation predict memory for recent spatial episodes.

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.

Peripheral sensitization is demonstrated in subacromial pain syndrome, with central sensitization found only in females.

The objective of this study was to explore whether hypersensitivity in patients with subacromial pain syndrome (SPS) manifests purely as localized peripheral sensitization or central sensitization, is influenced by the presence of subacromial pain, and presents similarly in male and female patients. Pressure pain threshold was assessed in both a patient cohort with unilateral SPS and an uninjured matched control group. Control subjects were assessed twice, with a 15 minute rest period between testing, while patients were assessed at baseline and after an almost instantaneous reduction in pain arising from an anesthetic injection in patients. Patients received a subacromial injection consisting of both anesthetics (3 cc of 2% lidocaine and 6 cc 0.5% Marcaine with Epinephrine) and a corticosteroid agent (1 cc DepoMedrol). Patients demonstrated hypersensitivity across the involved shoulder only, providing evidence for peripheral sensitization. There were trends for hypersensitivity across remote joints, however when separated by sex, only female patients demonstrated both peripheral and central sensitization. Immediate pain reduction had no influence on hypersensitivity in the short-term. Clinical Significance: Neuropathic components are likely present in some patients with subacromial pain syndrome, and female patients may be particularly at risk for presenting with neuropathic pain. These findings are applicable towards understanding the heterogeneous etiology underlying subacromial pain syndrome and informing clinical management.

Hippocampal and medial prefrontal ensemble spiking represents episodes and rules in similar task spaces.

Episodic memory requires the hippocampus and prefrontal cortex to guide decisions by representing events in spatial, temporal, and personal contexts. Both brain regions have been described by cognitive theories that represent events in context as locations in maps or memory spaces. We query whether ensemble spiking in these regions described spatial structures as rats performed memory tasks. From each ensemble, we construct a state-space with each point defined by the coordinated spiking of single and pairs of units in 125-ms bins and investigate how state-space locations discriminate task features. Trajectories through state-spaces correspond with behavioral episodes framed by spatial, temporal, and internal contexts. Both hippocampal and prefrontal ensembles distinguish maze locations, task intervals, and goals by distances between state-space locations, consistent with cognitive mapping and relational memory space theories of episodic memory. Prefrontal modulation of hippocampal activity may guide choices by directing memory representations toward appropriate state-space goal locations.

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

Memory modulates journey-dependent coding in the rat hippocampus.

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; 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.