Hippocampal motor memory network reorganization depends on familiarity, not time.

There is debate as to whether a time-dependent transformation of the episodic-like memory network is observed for nonepisodic tasks, including procedural motor memory. To determine how motor memory networks reorganize with time and practice, mice performed a motor task in a straight alley maze for 1 d (recent), 20 d of continuous training (continuous), or testing 20 d after the original training (remote), and then regional c-Fos expression was assessed. Elevated hippocampal c-Fos accompanied remote, but not continuous, motor task retrieval after 20 d, suggesting that the hippocampus remains engaged for nonhabitual remote motor memory retrieval.

Lipopolysaccharide-induced sickness behavior is not altered in male Fmr1-deficient mice.

OBJECTIVES: Fragile X syndrome is the main monogenetic cause of intellectual disability and autism. Alterations in the immune system are commonly found in these developmental disorders. We and others have demonstrated that Fmr1 mutant mice present an altered response to immune stimuli. However, whether this altered immune response can influence the Fmr1 mutant behavioral outcomes in response to inflammation has not been fully investigated. MATERIALS AND METHODS: In the current study, we examine the behavioral sickness response of male wildtype and knockout  mice to the innate immune stimulus lipopolysaccharide (LPS) (0.1 mg/kg) to determine if Fmr1 mutants have altered sickness behavior. We used an enzyme-linked immunosorbent assay (ELISA) to measure changes in the cytokine interleukin-6 (IL-6) to determine that inflammation was induced in the mice. Sickness behavior was assessed in a wheel-running paradigm, and a tail suspension test was used to assess the depressive-like phenotype that follows sickness behavior in response to LPS. RESULTS: The ELISA using blood serum confirmed a significant increase in IL-6 in mice that were treated with LPS. Treated Fmr1 mutants exhibited decreased distance traveled in the wheel running after LPS administration, similar to treated controls. Another cohort of animals treated with LPS were tested in the tail suspension test and exhibited no alterations in immobility time in response to LPS. CONCLUSION: Together, our data suggest that Fmr1 mutant mice do not have altered sickness behavior in response to a low dose of LPS.

Episodic Memory and Recollection Network Disruptions Following Chemotherapy Treatment in Breast Cancer Survivors: A Review of Neuroimaging Findings.

Long-term memory disturbances are amongst the most common and disruptive cognitive symptoms experienced by breast cancer survivors following chemotherapy. To date, most clinical assessments of long-term memory dysfunction in breast cancer survivors have utilized basic verbal and visual memory tasks that do not capture the complexities of everyday event memories. Complex event memories, including episodic memory and autobiographical memory, critically rely on hippocampal processing for encoding and retrieval. Systemic chemotherapy treatments used in breast cancer commonly cause neurotoxicity within the hippocampus, thereby creating a vulnerability to memory impairment. We review structural and functional neuroimaging studies that have identified disruptions in the recollection network and related episodic memory impairments in chemotherapy-treated breast cancer survivors, and argue for the need to better characterize hippocampally mediated memory dysfunction following chemotherapy treatments. Given the importance of autobiographical memory for a person's sense of identity, ability to plan for the future, and general functioning, under-appreciation of how this type of memory is impacted by cancer treatment can lead to overlooking or minimizing the negative experiences of breast cancer survivors, and neglecting a cognitive domain that may benefit from intervention strategies.

Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions.

A wide range of cognitive deficits, including memory loss associated with hippocampal dysfunction, have been widely reported in cancer survivors who received chemotherapy. Changes in both white matter and gray matter volume have been observed following chemotherapy treatment, with reduced volume in the medial temporal lobe thought to be due in part to reductions in hippocampal neurogenesis. Pre-clinical rodent models confirm that common chemotherapeutic agents used to treat various forms of non-CNS cancers reduce rates of hippocampal neurogenesis and impair performance on hippocampally-mediated learning and memory tasks. We review the pre-clinical rodent literature to identify how various chemotherapeutic drugs affect hippocampal neurogenesis and induce cognitive impairment. We also review factors such as physical exercise and environmental stimulation that may protect against chemotherapy-induced neurogenic suppression and hippocampal neurotoxicity. Finally, we review pharmacological interventions that target the hippocampus and are designed to prevent or reduce the cognitive and neurotoxic side effects of chemotherapy.

Social isolation induces hyperactivity and exploration in aged female mice.

Prolonged social isolation is associated with poor physical and mental health outcomes, findings observed in both humans, and rodent models of isolation. Humans, like mice, may engage in enhanced exploratory and social behaviour following isolation, which may protect against subsequent cognitive decline and psychological distress. Understanding how these effects may impact behaviour in older adults is particularly relevant, as this population is likely to experience periods of late-life social isolation. We report that late-life social isolation in female mice did not lead to robust depressive-like symptomology, altered social interaction behaviour, sensitivity to context fear acquisition and memory, or alterations in inflammatory cytokines (IL-6, IL-1ß, Tnf-α) or microglial activation (Itgam) within the hippocampus. Rather, isolation increased hyperactivity and exploration behaviours. These findings have translational value as the first female mouse model of late-life social isolation, and provide evidence to inform the development of interventions aimed at promoting functional recovery following isolation in late-life.

Reminders activate the prefrontal-medial temporal cortex and attenuate forgetting of event memory.

Replicas of an aspect of an experienced event can serve as effective reminders, yet little is known about the neural basis of such reminding effects. Here we examined the neural activity underlying the memory-enhancing effect of reminders 1 week after encoding of naturalistic film clip events. We used fMRI to determine differences in network activity associated with recently reactivated memories relative to comparably aged, non-reactivated memories. Reminders were effective in facilitating overall retrieval of memory for film clips, in an all-or-none fashion. Prefrontal cortex and hippocampus were activated during both reminders and retrieval. Peak activation in ventro-lateral prefrontal cortex (vPFC) preceded peak activation in the right hippocampus during the reminders. For film clips that were successfully retrieved after 7 days, pre-retrieval reminders did not enhance the quality of the retrieved memory or the number of details retrieved, nor did they more strongly engage regions of the recollection network than did successful retrieval of a non-reminded film clip. These results suggest that reminders prior to retrieval are an effective means of boosting retrieval of otherwise inaccessible episodic events, and that the inability to recall certain events after a delay of a week largely reflects a retrieval deficit, rather than a storage deficit for this information. The results extend other evidence that vPFC drives activation of the hippocampus to facilitate memory retrieval and scene construction, and show that this facilitation also occurs when reminder cues precede successful retrieval attempts. The time course of vPFC-hippocampal activity during the reminder suggests that reminders may first engage schematic information meditated by vPFC followed by a recollection process mediated by the hippocampus.

Reminders reinstate context-specificity to generalized remote memories in rats: relation to activity in the hippocampus and aCC.

Conditioned fear memories that are context-specific shortly after conditioning generalize over time. We exposed rats to a context reminder 30 d after conditioning, which served to reinstate context-specificity, and investigated how this reminder alters retrieval-induced activity in the hippocampus and anterior cingulate cortex (aCC) relative to a no reminder condition. c-Fos expression in dorsal CA1 was observed following retrieval in the original context, but not in a novel context, whether or not the memory was reactivated, suggesting that dCA1 retains the context-specific representation. c-Fos was highly expressed in aCC following remote memory testing in both contexts, regardless of reminder condition, indicating that aCC develops generalized representations that are insensitive to memory reactivation.

Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.

Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans.

The dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation.

The hippocampus and related neocortical structures in memory transformation.

Episodic memories are multifaceted and malleable, capable of being transformed with time and experience at both the neural level and psychological level. At the neural level, episodic memories are transformed from being dependent on the hippocampus to becoming represented in neocortical structures, such as the medial prefrontal cortex (mPFC), and back again, while at the psychological level, detailed, perceptually rich memories, are transformed to ones retaining only the gist of an experience or a schema related to it. Trace Transformation Theory (TTT) initially proposed that neural and psychological transformations are linked and proceed in tandem. Building on recent studies on the neurobiology of memory transformation in rodents and on the organization of the hippocampus and its functional cortical connectivity in humans, we present an updated version of TTT that is more precise and detailed with respect to the dynamic processes and structures implicated in memory transformation. At the heart of the updated TTT lies the long axis of the hippocampus whose functional differentiation and connectivity to neocortex make it a hub for memory formation and transformation. The posterior hippocampus, connected to perceptual and spatial representational systems in posterior neocortex, supports fine, perceptually rich, local details of memories; the anterior hippocampus, connected to conceptual systems in anterior neocortex, supports coarse, global representations that constitute the gist of a memory. Notable among the anterior neocortical structures is the medial prefrontal cortex (mPFC) which supports representation of schemas that code for common aspects of memories across different episodes. Linking the aHPC with mPFC is the entorhinal cortex (EC) which conveys information needed for the interaction/translation between gist and schemas. Thus, the long axis of the hippocampus, mPFC and EC provide the representational gradient, from fine to coarse and from perceptual to conceptual, that can implement processes implicated in memory transformation. Each of these representations of an episodic memory can co-exist and be in dynamic flux as they interact with one another throughout the memory's lifetime, going from detailed to schematic and possibly back again, all mediated by corresponding changes in neural representation.

Prior knowledge modulates the neural substrates of encoding and retrieving naturalistic events at short and long delays.

Congruence with prior knowledge and incongruence/novelty have long been identified as two prominent factors that, despite their opposing characteristics, can both enhance episodic memory. Using narrative film clip stimuli, this study investigated these effects in naturalistic event memories - examining behaviour and neural activation to help explain this paradox. Furthermore, we examined encoding, immediate retrieval, and one-week delayed retrieval to determine how these effects evolve over time. Behaviourally, both congruence with prior knowledge and incongruence/novelty enhanced memory for events, though incongruent events were recalled with more errors over time. During encoding, greater congruence with prior knowledge was correlated with medial prefrontal cortex (mPFC) and parietal activation, suggesting that these areas may play a key role in linking current episodic processing with prior knowledge. Encoding of increasingly incongruent events, on the other hand, was correlated with increasing activation in, and functional connectivity between, the medial temporal lobe (MTL) and posterior sensory cortices. During immediate and delayed retrieval the mPFC and MTL each demonstrated functional connectivity that varied based on the congruence of events with prior knowledge; with connectivity between the MTL and occipital regions found for incongruent events, while congruent events were associated with functional connectivity between the mPFC and the inferior parietal lobules and middle frontal gyri. These results demonstrate patterns of neural activity and connectivity that shift based on the nature of the event being experienced or remembered, and that evolve over time. Furthermore, they suggest potential mechanisms by which both congruence with prior knowledge and incongruence/novelty may enhance memory, through mPFC and MTL functional connectivity, respectively.

Neurobiological Mechanisms of Chemotherapy-induced Cognitive Impairment in a Transgenic Model of Breast Cancer.

Animal studies have reinforced clinical reports of cognitive impairment in cancer survivors following chemotherapy but, until now, all pre-clinical research in this area has been conducted on normal rodents. The present study investigated the effects of chemotherapy on cognition and underlying biological mechanisms in the FVB/N-Tg (MMTV-neu) 202 Mul/J mouse, a well-characterized transgenic model of breast cancer that has similarities to the tumorigenesis which occurs in humans. Tumor-bearing and control mice received three weekly injections of a combination of methotrexate + 5-fluorouracil, or an equal volume of saline. Different aspects of learning and memory were measured before and after treatment. The effects of tumor and chemotherapy on neurogenesis, neuro-inflammatory cytokine activity, and brain volume, as they relate to corresponding cognitive changes, were also measured. The toxic effects of chemotherapy extended to the cancerous model in which substantial cognitive impairment was also associated with the disease. Cognitive deficits were greatest in tumorigenic mice that received the anti-cancer drugs. Both tumor growth and chemotherapy caused significant changes in brain volume, including the hippocampus and frontal lobes, two structures that are directly implicated in cognitive tasks that were shown to be vulnerable. The level of hippocampal neurogenesis in adulthood was suppressed in chemotherapy-treated mice and associated with loss of hippocampus-controlled cognitive function. Dysregulation of cytokine activity was found in tumorigenic mice and associated with impaired cognitive performance. The results show that chemotherapy and tumor development independently contribute to cognitive deficits through different biological mechanisms.

Recovering and preventing loss of detailed memory: differential rates of forgetting for detail types in episodic memory.

Episodic memories undergo qualitative changes with time, but little is known about how different aspects of memory are affected. Different types of information in a memory, such as perceptual detail, and central themes, may be lost at different rates. In patients with medial temporal lobe damage, memory for perceptual details is severely impaired, while memory for central details is relatively spared. Given the sensitivity of memory to loss of details, the present study sought to investigate factors that mediate the forgetting of different types of information from naturalistic episodic memories in young healthy adults. The study investigated (1) time-dependent loss of "central" and "peripheral" details from episodic memories, (2) the effectiveness of cuing with reminders to reinstate memory details, and (3) the role of retrieval in preventing forgetting. Over the course of 7 d, memory for naturalistic events (film clips) underwent a time-dependent loss of peripheral details, while memory for central details (the core or gist of events) showed significantly less loss. Giving brief reminders of the clips just before retrieval reinstated memory for peripheral details, suggesting that loss of details is not always permanent, and may reflect both a storage and retrieval deficit. Furthermore, retrieving a memory shortly after it was encoded prevented loss of both central and peripheral details, thereby promoting retention over time. We consider the implications of these results for behavioral and neurobiological models of retention and forgetting.

Factors affecting graded and ungraded memory loss following hippocampal lesions.

This review evaluates three current theories--Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace-Transformation (Winocur, Moscovitch, & Bontempi, 2010)--in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed.

Hippocampal lesions produce both nongraded and temporally graded retrograde amnesia in the same rat.

Rats were administered contextual fear conditioning and trained on a water-maze, spatial memory task 28 days or 24 h before undergoing hippocampal lesion or control surgery. When tested postoperatively on both tasks, rats with hippocampal lesions exhibited retrograde amnesia for spatial memory at both delays but temporally graded retrograde amnesia for the contextual fear response. In demonstrating both types of retrograde amnesia in the same animals, the results parallel similar observations in human amnesics with hippocampal damage and provide compelling evidence that the nature of the task and the type of information being accessed are crucial factors in determining the pattern of retrograde memory loss associated with hippocampal damage. The results are interpreted as consistent with our transformation hypothesis (Winocur et al. (2010a) Neuropsychologia 48:2339-2356; Winocur and Moscovitch (2011) J Int Neuropsychol Soc 17:766-780) and at variance with standard consolidation theory and other theoretical models of memory.

Increasing CRTC1 function in the dentate gyrus during memory formation or reactivation increases memory strength without compromising memory quality.

Memory stabilization following encoding (synaptic consolidation) or memory reactivation (reconsolidation) requires gene expression and protein synthesis (Dudai and Eisenberg, 2004; Tronson and Taylor, 2007; Nader and Einarsson, 2010; Alberini, 2011). Although consolidation and reconsolidation may be mediated by distinct molecular mechanisms (Lee et al., 2004), disrupting the function of the transcription factor CREB impairs both processes (Kida et al., 2002; Mamiya et al., 2009). Phosphorylation of CREB at Ser133 recruits CREB binding protein (CBP)/p300 coactivators to activate transcription (Chrivia et al., 1993; Parker et al., 1996). In addition to this well known mechanism, CREB regulated transcription coactivators (CRTCs), previously called transducers of regulated CREB (TORC) activity, stimulate CREB-mediated transcription, even in the absence of CREB phosphorylation. Recently, CRTC1 has been shown to undergo activity-dependent trafficking from synapses and dendrites to the nucleus in excitatory hippocampal neurons (Ch'ng et al., 2012). Despite being a powerful and specific coactivator of CREB, the role of CRTC in memory is virtually unexplored. To examine the effects of increasing CRTC levels, we used viral vectors to locally and acutely increase CRTC1 in the dorsal hippocampus dentate gyrus region of mice before training or memory reactivation in context fear conditioning. Overexpressing CRTC1 enhanced both memory consolidation and reconsolidation; CRTC1-mediated memory facilitation was context specific (did not generalize to nontrained context) and long lasting (observed after virally expressed CRTC1 dissipated). CREB overexpression produced strikingly similar effects. Therefore, increasing CRTC1 or CREB function is sufficient to enhance the strength of new, as well as established reactivated, memories without compromising memory quality.

MEF2 negatively regulates learning-induced structural plasticity and memory formation.

Memory formation is thought to be mediated by dendritic-spine growth and restructuring. Myocyte enhancer factor 2 (MEF2) restricts spine growth in vitro, suggesting that this transcription factor negatively regulates the spine remodeling necessary for memory formation. Here we show that memory formation in adult mice was associated with changes in endogenous MEF2 levels and function. Locally and acutely increasing MEF2 function in the dentate gyrus blocked both learning-induced increases in spine density and spatial-memory formation. Increasing MEF2 function in amygdala disrupted fear-memory formation. We rescued MEF2-induced memory disruption by interfering with AMPA receptor endocytosis, suggesting that AMPA receptor trafficking is a key mechanism underlying the effects of MEF2. In contrast, decreasing MEF2 function in dentate gyrus and amygdala facilitated the formation of spatial and fear memory, respectively. These bidirectional effects indicate that MEF2 is a key regulator of plasticity and that relieving the suppressive effects of MEF2-mediated transcription permits memory formation.

Dorsal hippocampal CREB is both necessary and sufficient for spatial memory.

Although the transcription factor CREB has been widely implicated in memory, whether it is sufficient to produce spatial memory under conditions that do not normally support memory formation in mammals is unknown. We found that locally and acutely increasing CREB levels in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions that do not normally support spatial memory, weakly trained wild-type (WT) mice and strongly trained mutant mice with a brain-wide disruption of CREB function. Together with previous results, these findings indicate that CREB is both necessary and sufficient for spatial memory formation, and highlight its pivotal role in the hippocampal molecular machinery underlying the formation of spatial memory.