Enhancement of response learning in male rats with intrastriatal infusions of a BDNF - TrkB agonist, 7,8-dihydroxyflavone.

Enhancement of learning and memory by cognitive and physical exercise may be mediated by brain-derived neurotrophic factor (BDNF) acting at tropomyosin receptor kinase B (TrkB). Upregulation of BDNF and systemic administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), enhance learning of several hippocampus-sensitive tasks in rodents. Although BDNF and 7,8-DHF enhance functions of other brain areas too, these effects have mainly targeted non-cognitive functions. One goal of the present study was to determine whether 7,8-DHF would act beyond the hippocampus to enhance cognitive functions sensitive to manipulations of the striatum. Here, we examined the effects of intrastriatal infusions of 7,8-DHF on learning a striatum-sensitive response maze and on phosphorylation of TrkB receptors in 3-month-old male Sprague Dawley rats. Most prior studies of BDNF and 7,8-DHF effects on learning and memory have administered the drugs for days to months before assessing effects on cognition. A second goal of the present study was to determine whether a single drug treatment near the time of training would effectively enhance learning. Moreover, 7,8-DHF is often tested for its ability to reverse impairments in learning and memory rather than to enhance these functions in the absence of impairments. Thus, a third goal of this experiment was to evaluate the efficacy of 7,8-DHF in enhancing learning in unimpaired rats. In untrained rats, intrastriatal infusions of 7,8-DHF resulted in phosphorylation of TrkB receptors, suggesting that 7,8-DHF acted as a TrkB agonist and BDNF mimic. The findings that a single, intra-striatal infusion of 7,8-DHF 20 min before training enhanced response learning in rats suggest that, in addition to its trophic effects, BDNF modulates learning and memory through receptor mediated cell signaling events.

Single-Cell RNA Sequencing Reveals Immunomodulatory Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor Treatment in the Brains of Aged APP/PS1 Mice.

Alzheimer's disease (AD) leads to progressive neurodegeneration and dementia. AD primarily affects older adults with neuropathological changes including amyloid-beta (Aß) deposition, neuroinflammation, and neurodegeneration. We have previously demonstrated that systemic treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) reduces the Aß load, increases Aß uptake by activated microglia and macrophages, reduces neuroinflammation, and restores dendrites and synapses in the brains of aged APPswe/PS1dE9 (APP/PS1) mice. However, the mechanisms underlying SCF+G-CSF-enhanced brain repair in aged APP/PS1 mice remain unclear. This study used a transcriptomic approach to identify the potential mechanisms by which SCF+G-CSF treatment modulates microglia and peripheral myeloid cells to mitigate AD pathology in the aged brain. After injections of SCF+G-CSF for 5 consecutive days, single-cell RNA sequencing was performed on CD11b+ cells isolated from the brains of 28-month-old APP/PS1 mice. The vast majority of cell clusters aligned with transcriptional profiles of microglia in various activation states. However, SCF+G-CSF treatment dramatically increased a cell population showing upregulation of marker genes related to peripheral myeloid cells. Flow cytometry data also revealed an SCF+G-CSF-induced increase of cerebral CD45high/CD11b+ active phagocytes. SCF+G-CSF treatment robustly increased the transcription of genes implicated in immune cell activation, including gene sets that regulate inflammatory processes and cell migration. The expression of S100a8 and S100a9 was robustly enhanced following SCF+G-CSF treatment in all CD11b+ cell clusters. Moreover, the topmost genes differentially expressed with SCF+G-CSF treatment were largely upregulated in S100a8/9-positive cells, suggesting a well-conserved transcriptional profile related to SCF+G-CSF treatment in resident and peripherally derived CD11b+ immune cells. This S100a8/9-associated transcriptional profile contained notable genes related to pro-inflammatory and anti-inflammatory responses, neuroprotection, and Aß plaque inhibition or clearance. Altogether, this study reveals the immunomodulatory effects of SCF+G-CSF treatment in the aged brain with AD pathology, which will guide future studies to further uncover the therapeutic mechanisms.

Hippocampus-sensitive and striatum-sensitive learning one month after morphine or cocaine exposure in male rats.

These experiments examined whether morphine and cocaine alter the balance between hippocampal and striatal memory systems measured long after drug exposure. Male rats received injections of morphine (5 mg/kg), cocaine (20 mg/kg), or saline for five consecutive days. One month later, rats were trained to find food on a hippocampus-sensitive place task or a striatum-sensitive response task. Relative to saline controls, morphine-treated rats exhibited impaired place learning but enhanced response learning; prior cocaine exposure did not significantly alter learning on either task. Another set of rats was trained on a dual-solution T-maze that can be solved with either place or response strategies. While a majority (67%) of control rats used place solutions, morphine treatment one month prior resulted in the exclusive use of response solutions (100%). Prior cocaine treatment did not significantly alter strategy selection. Molecular markers related to learning and drug abuse were measured in the hippocampus and striatum one month after drug exposure in behaviorally untested rats. Protein levels of glial-fibrillary acidic protein (GFAP), an intermediate filament specific to astrocytes, increased significantly in the hippocampus after morphine exposure, but not after cocaine exposure. Exposure to morphine or cocaine did not significantly change levels of brain-derived neurotrophic factor (BDNF) or a downstream target of BDNF signaling, glycogen synthase kinase 3ß (GSK3ß), in the hippocampus or striatum. Thus, exposure to morphine resulted in a long-lasting shift from hippocampal toward striatal dominance during learning, an effect that may be associated with lasting alterations in hippocampal astrocytes. Cocaine produced changes in the same direction, suggesting that use of a higher dose or longer duration of exposure might produce effects comparable to those seen with morphine.

Autobiographical Memory Content and Recollection Frequency: Public Release of Quantitative Datasets and Representative Classification Analysis.

Autobiographical memory (AM), the recollection of personally-experienced events, has several adaptive functions and has been studied across numerous dimensions. We previously introduced two methods to quantify across the life span AM content (the amount and types of retrieved details) and the everyday occurrence of its recollection. The CRAM (cue-recalled autobiographical memory) test used naturalistic word prompts to elicit AMs. Subjects dated the memories to life periods and reported the numbers of details recalled across eight features (e.g., spatial detail, temporal detail, people, and emotions). In separate subjects, an experience sampling method quantified in everyday settings the frequency of AM retrieval and of mental representation of future personal events or actions (termed prospective memory: PM); these data permit evaluation of the temporal orientation of episodic recollection. We describe these datasets now publicly released in open access (CRAM: doi.org/10.6084/m9.figshare.10246958; AM-PM experience-sampling: doi.org/10.6084/m9.figshare.10246940). We also present examples of data mining, using cluster analyses of CRAM (14,242 AMs scored for content from 4,244 subjects). Analysis of raw feature scores yielded three AM clusters separated by total recalled content. Normalizing for total content revealed three classes of AM based on the relative contributions of each feature: AMs containing a relatively large number of details related to people, AMs containing a high degree of spatial information, and AMs with details equally distributed across features. Differences in subject age, memory age, and total content were detected across feature clusters. These findings highlight the value in additional mining of these datasets to further our understanding of autobiographical recollection.

Inactivation of the striatum in aged rats rescues their ability to learn a hippocampus-sensitive spatial navigation task.

Studies of age-related changes in learning and memory often focus on hippocampus-sensitive tasks and reveal age-associated impairments across numerous species and contexts. However, cognitive decline with advanced age is not all-encompassing; for example, forms of striatum-sensitive learning are conserved or enhanced with age. Under certain conditions, hippocampal and striatal memory systems function in opposition. In young adult rodents, disruption of one structure can enhance learning on tasks dependent on the other, suggesting that competitive interactions across memory systems contribute to learning and memory abilities. This report examines whether imbalances across memory systems might contribute to cognitive aging. We inactivated the striatum using central infusions of lidocaine (sodium channel blocker) prior to hippocampus-sensitive spatial (place) training in young (3-4-month-old) and old (24-25-month-old) F344 male rats. Consistent with prior work, vehicle-infused old rats exhibited place learning impairments relative to young rats. Additionally, striatal inactivation enhanced learning in old rats, but not young rats, abolishing the age-related impairment. These findings suggest that age-related declines in learning tasks thought to engage the hippocampus may stem from exaggerated interference from other memory systems and that interventions to target the striatum may reverse some age-related learning decrements.

Involvement of lactate transport in two object recognition tasks that require either the hippocampus or striatum.

Growing evidence indicates that hippocampal lactate, released from astrocytes, is an important regulator of learning and memory processing. This study evaluated the selective involvement of hippocampal and striatal lactate in two object recognition tasks. The tasks tested recognition memory after a change in location of two target objects (double object location; dOL) or after replacement of familiar targets with two new objects set in the original locations (double object replacement; dOR). Rats received three study sessions across which exploration times decreased. The recognition index was the change in exploration time of both objects on a test trial from the exploration times on the final study trial. We first verified a double dissociation between hippocampus and striatum across these tasks. The sodium channel blocker, lidocaine, was infused into one of the two brain regions after the study sessions and before the test trial. To test the role of neuronal lactate in recognition memory, an inhibitor of the neuronal lactate transporter, α-cyano-4-hydroxycinnamate (4-CIN), was similarly infused. For both drugs, infusions into the hippocampus but not the striatum impaired recognition in the dOL, whereas infusions into the striatum but not hippocampus impaired recognition in the dOR. The findings obtained with 4-CIN demonstrate for the first time the importance of neuronal lactate uptake in the hippocampus and the striatum for object recognition memory processing. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Differential Arc expression in the hippocampus and striatum during the transition from attentive to automatic navigation on a plus maze.

The strategies utilized to effectively perform a given task change with practice and experience. During a spatial navigation task, with relatively little training, performance is typically attentive enabling an individual to locate the position of a goal by relying on spatial landmarks. These (place) strategies require an intact hippocampus. With task repetition, performance becomes automatic; the same goal is reached using a fixed response or sequence of actions. These (response) strategies require an intact striatum. The current work aims to understand the activation patterns across these neural structures during this experience-dependent strategy transition. This was accomplished by region-specific measurement of activity-dependent immediate early gene expression among rats trained to different degrees on a dual-solution task (i.e., a task that can be solved using either place or response navigation). As expected, rats increased their reliance on response navigation with extended task experience. In addition, dorsal hippocampal expression of the immediate early gene Arc was considerably reduced in rats that used a response strategy late in training (as compared with hippocampal expression in rats that used a place strategy early in training). In line with these data, vicarious trial and error, a behavior linked to hippocampal function, also decreased with task repetition. Although Arc mRNA expression in dorsal medial or lateral striatum alone did not correlate with training stage, the ratio of expression in the medial striatum to that in the lateral striatum was relatively high among rats that used a place strategy early in training as compared with the ratio among over-trained response rats. Altogether, these results identify specific changes in the activation of dissociated neural systems that may underlie the experience-dependent emergence of response-based automatic navigation.

Older adults report moderately more detailed autobiographical memories.

Autobiographical memory (AM) is an essential component of the human mind. Although the([A-z]+) amount and types of subjective detail (content) that compose AMs constitute important dimensions of recall, age-related changes in memory content are not well characterized. Previously, we introduced the Cue-Recalled Autobiographical Memory test (CRAM; see http://cramtest.info), an instrument that collects subjective reports of AM content, and applied it to college-aged subjects. CRAM elicits AMs using naturalistic word-cues. Subsequently, subjects date each cued AM to a life period and count the number of remembered details from specified categories (features), e.g., temporal detail, spatial detail, persons, objects, and emotions. The current work applies CRAM to a broad range of individuals (18-78 years old) to quantify the effects of age on AM content. Subject age showed a moderately positive effect on AM content: older compared with younger adults reported ∼16% more details (∼25 vs. ∼21 in typical AMs). This age-related increase in memory content was similarly observed for remote and recent AMs, although content declined with the age of the event among all subjects. In general, the distribution of details across features was largely consistent among younger and older adults. However, certain types of details, i.e., those related to objects and sequences of events, contributed more to the age effect on content. Altogether, this work identifies a moderate age-related feature-specific alteration in the way life events are subjectively recalled, among an otherwise stable retrieval profile.

The natural frequency of human prospective memory increases with age.

Autobiographical memory (AM), the recollection of past experiences, and prospective memory (PM), the prospection of future events, are prominent components of subjective life, yet data on the frequencies of their occurrence are limited. Using experience sampling, we quantified the incidence of AM and PM in natural settings among various age groups. Individuals of all ages reported engaging in AM approximately 10% of the time. In contrast, whereas younger subjects recalled PMs as often as they recalled AMs, older subjects experienced PM twice as frequently. AM occurrence was positively correlated with PM occurrence, most strongly among younger individuals. AM and PM durations were also positively correlated and remarkably stable across age groups. Together, these data identify an age-associated shift in the temporal orientation of recollection and quantify the relationship between AM and PM. More broadly, this approach provides a quantitative foundation of AM and PM occurrence, a crucial yet largely unexplored dimension of recollection.

A secondary working memory challenge preserves primary place strategies despite overtraining.

Learning by repetition engages distinct cognitive strategies whose contributions are adjusted with experience. Early in learning, performance relies upon flexible, attentive strategies. With extended practice, inflexible, automatic strategies emerge. This transition is thought fundamental to habit formation and applies to human and animal cognition. In the context of spatial navigation, place strategies are flexible, typically employed early in training, and rely on the spatial arrangement of landmarks to locate a goal. Response strategies are inflexible, become dominant after overtraining, and utilize fixed motor sequences. Although these strategies can operate independently, they have also been shown to interact. However, since previous work has focused on single-choice learning, if and how these strategies interact across sequential choices remains unclear. To test strategy interactions across sequential choices, we utilized various two-choice spatial navigation tasks administered on the Opposing Ts maze, an apparatus for rodents that permits experimental control over strategy recruitment. We found that when a second choice required spatial working memory, the transition to response navigation on the first choice was blocked. Control experiments specified this effect to the cognitive aspects of the secondary task. In addition, response navigation, once established on a single choice, was not reversed by subsequent introduction of a secondary choice reliant on spatial working memory. These results demonstrate that performance strategies interact across choices, highlighting the sensitivity of strategy use to the cognitive demands of subsequent actions, an influence from which overtrained rigid actions may be protected.

Quantitative measurements of autobiographical memory content.

Autobiographical memory (AM), subjective recollection of past experiences, is fundamental in everyday life. Nevertheless, characterization of the spontaneous occurrence of AM, as well as of the number and types of recollected details, remains limited. The CRAM (Cue-Recalled Autobiographical Memory) test (http://cramtest.info) adapts and combines the cue-word method with an assessment that collects counts of details recalled from different life periods. The SPAM (Spontaneous Probability of Autobiographical Memories) protocol samples introspection during everyday activity, recording memory duration and frequency. These measures provide detailed, naturalistic accounts of AM content and frequency, quantifying essential dimensions of recollection. AM content (∼20 details/recollection) decreased with the age of the episode, but less drastically than the probability of reporting remote compared to recent memories. AM retrieval was frequent (∼20/hour), each memory lasting ∼30 seconds. Testable hypotheses of the specific content retrieved in a fixed time from given life periods are presented.

Interdependent group contingency management for cocaine-dependent methadone maintenance patients.

Contingency management (CM) for drug abstinence has been applied to individuals independently even when delivered in groups. We developed a group CM intervention in which the behavior of a single, randomly selected, anonymous individual determined reinforcement delivery for the entire group. We also compared contingencies placed only on cocaine abstinence (CA) versus one of four behaviors (CA, treatment attendance, group CM attendance, and methadone compliance) selected randomly at each drawing. Two groups were formed with 22 cocaine-dependent community-based methadone patients and exposed to both CA and multiple behavior (MB) conditions in a reversal design counterbalanced across groups for exposure order. The group CM intervention proved feasible and safe. The MB condition improved group CM meeting attendance relative to the CA condition.