Context memory formed in medial prefrontal cortex during infancy enhances learning in adulthood.

Adult behavior is commonly thought to be shaped by early-life experience, although episodes experienced during infancy appear to be forgotten. Exposing male rats during infancy to discrete spatial experience we show that these rats in adulthood are significantly better at forming a spatial memory than control rats without such infantile experience. We moreover show that the adult rats' improved spatial memory capability is mainly based on memory for context information during the infantile experiences. Infantile spatial experience increased c-Fos activity at memory testing during adulthood in the prelimbic medial prefrontal cortex (mPFC), but not in the hippocampus. Inhibiting prelimbic mPFC at testing during adulthood abolished the enhancing effect of infantile spatial experience on learning. Adult spatial memory capability only benefitted from spatial experience occurring during the sensitive period of infancy, but not when occurring later during childhood, and when sleep followed the infantile experience. In conclusion, the infantile brain, by a sleep-dependent mechanism, favors consolidation of memory for the context in which episodes are experienced. These representations comprise mPFC regions and context-dependently facilitate learning in adulthood.

Rearing is critical for forming spatial representations in pre-weanling rats.

Rearing, i.e., standing on the hind limbs in an upright posture, is part of a rat's innate exploratory motor program. Here, we examined in developing rats whether rearing is critical for the pup's capability to form spatial representations based on distal environmental cues. Pups (male) were tested at PD18, i.e., the first day they typically exhibit stable rearing, on a spatial habituation paradigm comprising a Familiarization session (with the pup exposed to an arena with a specific configuration of distal cues) followed, 3 h later, by a Test session where the pups were either re-exposed to the identical distal cue configuration (NoChange) or a changed configuration (DistalChange). In Experiment 1, rearing activity (rearing events, duration) decreased from Familiarization to Test in the NoChange pups but, remained elevated in the DistalChange group indicating that these pups recognized the distal novelty. Recognition of distal novelty was associated with increased c-Fos expression in hippocampal and medial prefrontal cortex (mPFC) areas, compared with NoChange pups. Analysis of GAD67+ cells suggested a parallel increase in excitation and inhibition specifically in prelimbic mPFC networks in response to distal cue changes. In Experiment 2, the pups were mechanically prevented from rearing while still seeing the distal cues during Familiarization. Rearing activity in the Test session of these pups did not differ between groups that were or were not exposed to a changed distal cue configuration at Test. The findings evidence a critical role of rearing for the emergence of allocentric representations integrating distal space during early development.

Two distinct ways to form long-term object recognition memory during sleep and wakefulness.

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

Short-term high-fat feeding induces a reversible net decrease in synaptic AMPA receptors in the hypothalamus.

Dietary obesity compromises brain function, but the effects of high-fat food on synaptic transmission in hypothalamic networks, as well as their potential reversibility, are yet to be fully characterized. We investigated the impact of high-fat feeding on a hallmark of synaptic plasticity, i.e., the expression of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) that contain the subunits GluA1 and GluA2, in hypothalamic and cortical synaptoneurosomes of male rats. In the main experiment (experiment 1), three days, but not one day of high-fat diet (HFD) decreased the levels of AMPAR GluA1 and GluA2 subunits, as well as GluA1 phosphorylation at Ser845, in hypothalamus but not cortex. In experiment 2, we compared the effects of the three-day HFD with those a three-day HFD followed by four recovery days of normal chow. This experiment corroborated the suppressive effect of high-fat feeding on hypothalamic but not cortical AMPAR GluA1, GluA2, and GluA1 phosphorylation at Ser845, and indicated that the effects are reversed by normal-chow feeding. High-fat feeding generally increased energy intake, body weight, and serum concentrations of insulin, leptin, free fatty acids, and corticosterone; only the three-day HFD increased wakefulness assessed via video analysis. Results indicate a reversible down-regulation of hypothalamic glutamatergic synaptic strength in response to short-term high-fat feeding. Preceding the manifestation of obesity, this rapid change in glutamatergic neurotransmission may underlie counter-regulatory efforts to prevent excess body weight gain, and therefore, represent a new target of interventions to improve metabolic control.

Deepened sleep makes hippocampal spatial memory more persistent.

Ample evidence has indicated a beneficial role of sleep, and particularly of slow wave sleep (SWS) in memory consolidation. However, how basic features of sleep, its depth and duration, contribute to this process remained elusive. Here, we investigated spatial object-place recognition (OPR) memory in rats, to systematically dissociate effects of sleep depth and duration on the formation of recent and remote hippocampus-dependent memory. Encoding of the spatial configuration was followed by an experimental post-encoding period of either 2 or 4 h, during which the rats had either "regular sleep", "deeper sleep", or were kept awake. A deeper sleep was achieved by an extended habituation of the rats to the sleep environment. Retrieval was tested either immediately after the 2-hour post-encoding period (recent memory test) or 1 week later (remote memory test). Deeper sleep expressed itself in a selective increase in the time spent in SWS, and in numbers of slow oscillations, spindles, and hippocampal ripples during SWS, whereas preREM and REM sleep were not affected. At the recent test, OPR memory was preserved only after sleep, but independent of its depth. At the remote test, however, OPR memory was preserved only after deeper sleep, whereas the wake and the regularly sleeping rats did not show remote OPR memory, even with the longer 4-h post-encoding period. Our results indicate that, rather than a longer duration, deeper sleep, i.e., a longer time in SWS together with enhanced oscillatory signatures of mnemonic processing during this sleep stage, occurring within a 2-hour window after encoding, is the factor that makes hippocampus-dependent memory more persistent.

Sleep-dependent consolidation patterns reveal insights into episodic memory structure.

Episodic memory formation is considered a genuinely hippocampal function. Its study in rodents has relied on two different task paradigms, i.e. the so called "what-where-when" (WW-When) task and "what-where-which" (WW-Which) task. The WW-When task aims to assess the memory for an episode as an event bound into its context defined by spatial and distinct temporal information, the WW-Which task lacks the temporal component and introduces, instead, an "occasion setter" marking the broader contextual configuration in which the event occurred. Whether both tasks measure episodic memory in an equivalent manner in terms of recollection has been controversially discussed. Here, we compared in two groups of rats the consolidating effects of sleep on episodic-like memory between both task paradigms. Sampling and test phases were separated by a 90-min morning retention interval which did or did not allow for spontaneous sleep. Results show that sleep is crucial for the consolidation of the memory on both tasks. However, consolidating effects of sleep were stronger for the WW-Which than WW-When task. Comparing performance during the post-sleep test phase revealed that WW-When memory only gradually emerged during the 3-min test period whereas WW-Which memory was readily expressed already from the first minute onward. Separate analysis of the temporal and spatial components of WW-When performance showed that the delayed episodic memory on this task originated from the temporal component which also did not emerge until the third minute of the test phase, whereas the spatial component already showed up in the first minute. In conclusion, sleep differentially affects consolidation on the two episodic-like memory tasks, with the delayed expression of WW-When memory after sleep resulting from preferential coverage of temporal aspects by this task.

The hippocampus is crucial for forming non-hippocampal long-term memory during sleep.

There is a long-standing division in memory research between hippocampus-dependent memory and non-hippocampus-dependent memory, as only the latter can be acquired and retrieved in the absence of normal hippocampal function1,2. Consolidation of hippocampus-dependent memory, in particular, is strongly supported by sleep3-5. Here we show that the formation of long-term representations in a rat model of non-hippocampus-dependent memory depends not only on sleep but also on activation of a hippocampus-dependent mechanism during sleep. Rats encoded non-hippocampus-dependent (novel-object recognition6-8) and hippocampus-dependent (object-place recognition) memories before a two-hour period of sleep or wakefulness. Memory was tested either immediately thereafter or remotely (after one or three weeks). Whereas object-place recognition memory was stronger for rats that had slept after encoding (rather than being awake) at both immediate and remote testing, novel-object recognition memory profited from sleep only three weeks after encoding, at which point it was preserved in rats that had slept after encoding but not in those that had been awake. Notably, inactivation of the hippocampus during post-encoding sleep by intrahippocampal injection of muscimol abolished the sleep-induced enhancement of remote novel-object recognition memory. By contrast, muscimol injection before remote retrieval or memory encoding had no effect on test performance, confirming that the encoding and retrieval of novel-object recognition memory are hippocampus-independent. Remote novel-object recognition memory was associated with spindle activity during post-encoding slow-wave sleep, consistent with the view that neuronal memory replay during slow-wave sleep contributes to long-term memory formation. Our results indicate that the hippocampus has an important role in long-term consolidation during sleep even for memories that have previously been considered hippocampus-independent.

Sleep Enhances Recognition Memory for Conspecifics as Bound into Spatial Context.

Social memory refers to the fundamental ability of social species to recognize their conspecifics in quite different contexts. Sleep has been shown to benefit consolidation, especially of hippocampus-dependent episodic memory whereas effects of sleep on social memory are less well studied. Here, we examined the effect of sleep on memory for conspecifics in rats. To discriminate interactions between the consolidation of social memory and of spatial context during sleep, adult Long Evans rats performed on a social discrimination task in a radial arm maze. The Learning phase comprised three 10-min sampling sessions in which the rats explored a juvenile rat presented at a different arm of the maze in each session. Then the rats were allowed to sleep (n = 18) or stayed awake (n = 18) for 120 min. During the following 10-min Test phase, the familiar juvenile rat (of the Learning phase) was presented along with a novel juvenile rat, each rat at an opposite arm of the maze. Significant social recognition memory, as indicated by preferential exploration of the novel over the familiar conspecific, occurred only after post-learning sleep, but not after wakefulness. Sleep, compared with wakefulness, significantly enhanced social recognition during the first minute of the Test phase. However, memory expression depended on the spatial configuration: Significant social recognition memory emerged only after sleep when the rat encountered the novel conspecific at a place different from that of the familiar juvenile in the last sampling session before sleep. Though unspecific retrieval-related effects cannot entirely be excluded, our findings suggest that sleep, rather than independently enhancing social and spatial aspects of memory, consolidates social memory by acting on an episodic representation that binds the memory of the conspecific together with the spatial context in which it was recently encountered.