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The prefrontal cortex (PFC) is crucial for accurate memory performance when prior knowledge interferes with new learning, but the mechanisms that minimize proactive interference are unknown. To investigate these, we assessed the influence of medial PFC (mPFC) activity on spatial learning and hippocampal coding in a plus maze task that requires both structures. mPFC inactivation did not impair spatial learning or retrieval per se, but impaired the ability to follow changing spatial rules. mPFC and CA1 ensembles recorded simultaneously predicted goal choices and tracked changing rules; inactivating mPFC attenuated CA1 prospective coding. mPFC activity modified CA1 codes during learning, which in turn predicted how quickly rats adapted to subsequent rule changes. The results suggest that task rules signaled by the mPFC become incorporated into hippocampal representations and support prospective coding. By this mechanism, mPFC activity prevents interference by "teaching" the hippocampus to retrieve distinct representations of similar circumstances. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Adapting successfully to new situations relies on integrating memory of similar circumstances with the outcomes of past actions. Here,we tested how reward history and recent memory influenced coding by orbital prefrontal cortex (OFC) neurons. Rats were trained to find food in plus maze tasks that required both the OFC and the hippocampus, and unit activity was recorded during stable performance, reversal learning, and strategy switching. OFC firing distinguished different rewarded paths, journeys from a start arm to a goal arm. Activity of individual cells and the population correlated with performance as rats learned newly rewarded outcomes. Activity was similar during reversal, an OFC-dependent task, and strategy switching, an OFC-independent task, suggesting that OFC associates information about paths and outcomes both when it is required for performance and when it is not. Path-selective OFC cells fired differently during overlapping journeys that led to different goals or from different starts, resembling journey-dependent coding by hippocampal neurons. Local field potentials (LFPs) recorded simultaneously in the OFC and the hippocampus oscillated coherently in the theta band (5-12 Hz) during stable performance. LFP coherence diminished when rats adapted to altered reward contingencies and followed different paths. Thus, OFC neurons appear to participate in a distributed network including the hippocampus that associates spatial paths, recent memory, and integrated reward history. [ABSTRACT FROM AUTHOR]

Prelimbic-infralimbic cortex (PL-IL) and orbitofrontal cortex (OFC) influence behavioral flexibility in the rat. The authors tested the effects of PL-IL or OFC infusion with the GABA agonist muscimol in the context of 2 flexible responding tasks: strategy switching and reversal. Muscimol infusion into PL-IL impaired retention of strategy switches but not reversals, whereas muscimol infusion into OFC impaired retention of reversals but not switches. However, whereas training in repeated reversals did not remove the requirement of PL-IL for switch retention (E. L. Rich & M. L. Shapiro, 2007), training in repeated switches did remove the requirement of OFC for reversal retention. Thus, activity during strategy switches was sufficient to initiate learning and remove the requirement of OFC in later reversals. [ABSTRACT FROM AUTHOR]

The immediate-early gene (IEG) Arc is transcribed after behavioral and physiological treatments that induce synaptic plasticity and is implicated in memory consolidation. The relative contributions of neuronal activity and learning-related plasticity to the behavioral induction of Arc remain to be defined. To differentiate the contributions of each, we assessed the induction of Arc transcription in rats with fornix lesions that impair hippocampal learning yet leave cortical connectivity and neuronal firing essentially intact. Arc expression was assessed after exploration of novel environments and performance of a novel water maze task during which normal rats learned the spatial location of an escape platform. During the same task, rats with fornix lesions learned to approach a visible platform but did not learn its spatial location. Rats with fornix lesions had normal baseline levels of hippocampal Arc mRNA, but unlike normal rats, expression was not increased in response to water maze training. The integrity of signaling pathways controlling Arc expression was demonstrated by stimulation of the medial perforant path, which induced normal synaptic potentiation and Arc in rats with fornix lesions. Together, the results demonstrate that Arc induction can be decoupled from behavior and is more likely to indicate the engagement of synaptic plasticity mechanisms than synaptic or neuronal activity per se. The results further imply that fornix lesions may impair memory in part by decoupling neuronal activity from signaling pathways required for long-lasting hippocampal synaptic plasticity. [ABSTRACT FROM AUTHOR]

Tests rats given N-methyl-Daspartate (NMDA) antagonits in the radial maze in spatial working memory (WM) and reference memory (RM) tasks. Comparison between female and male rats; Mnemonic effects of NMDA antagonits.

In this issue of Neuron, MacDonald et al. describe hippocampal “time cells” that fire during specific delay periods as rats performed a memory task. Converging results in monkeys suggest that the hippocampus encodes episodes by signaling events in time. [ABSTRACT FROM AUTHOR]

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3-deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3-deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]