NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning.

Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily conditioning using local microinfusion of the GABA(A) receptor agonist muscimol or the NMDA receptor antagonist APV into the rat mPFC. Muscimol infusions into the mPFC before daily conditioning significantly retarded CR acquisition and reduced CR expression if applied after sufficient learning. APV infusion also impaired acquisition of CRs, but not expression of well-learned CRs. When infusions were made immediately after daily conditioning, acquisition of the CR was partially impaired in both the muscimol and APV infusion groups. In contrast, rats that received muscimol infusions 3 h after daily conditioning exhibited improvement in their CR performance comparable to that of the control group. Both the pre- and post-conditioning infusion of muscimol had no effect on acquisition in the delay paradigm. These results suggest that the mPFC participates in both acquisition of a CR and the early stage of consolidation of memory in trace, but not delay eyeblink conditioning by NMDA receptor-mediated operations

Systems consolidation requires postlearning activation of NMDA receptors in the medial prefrontal cortex in trace eyeblink conditioning.

The importance of the hippocampus in declarative memory is limited to recently acquired memory, and remotely acquired memory is believed to be stored somewhere in the neocortex. However, it remains unknown how the memory network is reorganized from a hippocampus-dependent form into a neocortex-dependent one. We reported previously that the medial prefrontal cortex (mPFC) is important for this neocortex-dependent remote memory in rat trace eyeblink conditioning. Here, we investigate the involvement of NMDA receptors in the mPFC in this reorganization and determine the time window of their contribution using chronic infusion of an antagonist into the mPFC, specifically during the postlearning consolidation period. The rats with blockade of the mPFC NMDA receptors during the first 1 or 2 weeks after learning showed a marked impairment in memory retention measured 6 weeks after learning, but relearned normally with subsequent conditioning. In contrast, the same treatment had no effect if it was performed during the third to fourth weeks or during the first day just after learning. The specificity of NMDA receptor blockade was confirmed by the reduced long-term potentiation in the hippocampal-prefrontal pathway in these rats. These results suggest that successful establishment of remotely acquired memory requires activation of NMDA receptors in the mPFC during at least the initial week of the postlearning period. Such NMDA receptor-dependent processes may mediate the maturation of neocortical networks that underlies permanent memory storage and serve as a way to reorganize memory circuitry to the neocortex-dependent form

The impact of experienced stress on aged spatial discrimination: Cortical overreliance as a result of hippocampal impairment

A large body of neuroscientific work indicates that exposure to experienced stress causes damage to both cortical and hippocampal cells and results in impairments to cognitive abilities associated with these structures. Similarly, work within the domain of cognitive aging demonstrates that elderly participants who report experiencing greater amounts of stress show reduced levels of cognitive functioning. The present article attempted to combine both findings by collecting data from elderly and young participants who completed a spatial discrimination paradigm developed by Reagh and colleagues [Reagh et al. (2013) Hippocampus 24:303-314] to measure hippocampal-mediated cognitive processes. In order to investigate the effect of stress on the cortex and, indirectly, the hippocampus, it paired the paradigm with electroencephalographic recordings of the theta frequency band, which is thought to reflect cortical/hippocampal interactions. Findings revealed that elderly participants with high levels of experienced stress performed significantly worse on target recognition and lure discrimination and demonstrated heightened levels of cortical theta synchronization compared with young and elderly low stress counterparts. Results therefore provided further evidence for the adverse effect of stress on cognitive aging and indicate that impaired behavioral performance among high stress elderly may coincide with an overreliance on cortical cognitive processing strategies as a result of early damage to the hippocampus

The spontaneous electrical activity of neurons in leech ganglia

Using the newly developed voltage-sensitive dye VF2.1.Cl, we monitored simultaneously the spontaneous electrical activity of 3c80 neurons in a leech ganglion, representing around 20% of the entire neuronal population. Neurons imaged on the ventral surface of the ganglion either fired spikes regularly at a rate of 1-5 Hz or fired sparse spikes irregularly. In contrast, neurons imaged on the dorsal surface, fired spikes in bursts involving several neurons. The overall degree of correlated electrical activity among leech neurons was limited in control conditions but increased in the presence of the neuromodulator serotonin. The spontaneous electrical activity in a leech ganglion is segregated in three main groups: neurons comprising Retzius cells, Anterior Pagoda, and Annulus Erector motoneurons firing almost periodically, a group of neurons firing sparsely and randomly, and a group of neurons firing bursts of spikes of varying durations. These three groups interact and influence each other only weakly

Hippocampal state-dependent behavioral reflex to an identical sensory input in rats.

We examined the local field potential of the hippocampus to monitor brain states during a conditional discrimination task, in order to elucidate the relationship between ongoing brain states and a conditioned motor reflex. Five 10-week-old Wistar/ST male rats underwent a serial feature positive conditional discrimination task in eyeblink conditioning using a preceding light stimulus as a conditional cue for reinforced trials. In this task, a 2-s light stimulus signaled that the following 350-ms tone (conditioned stimulus) was reinforced with a co-terminating 100-ms periorbital electrical shock. The interval between the end of conditional cue and the onset of the conditioned stimulus was 4±1 s. The conditioned stimulus was not reinforced when the light was not presented. Animals successfully utilized the light stimulus as a conditional cue to drive differential responses to the identical conditioned stimulus. We found that presentation of the conditional cue elicited hippocampal theta oscillations, which persisted during the interval of conditional cue and the conditioned stimulus. Moreover, expression of the conditioned response to the tone (conditioned stimulus) was correlated with the appearance of theta oscillations immediately before the conditioned stimulus. These data support hippocampal involvement in the network underlying a conditional discrimination task in eyeblink conditioning. They also suggest that the preceding hippocampal activity can determine information processing of the tone stimulus in the cerebellum and its associated circuits

Methylphenidate during early consolidation affects long-term associative memory retrieval depending on baseline catecholamines

RATIONALE: Synaptic memory consolidation is thought to rely on catecholaminergic signaling. Eventually, it is followed by systems consolidation, which embeds memories in a neocortical network. Although this sequence was demonstrated in rodents, it is unclear how catecholamines affect memory consolidation in humans. OBJECTIVES: Here, we tested the effects of catecholaminergic modulation on synaptic and subsequent systems consolidation. We expected enhanced memory performance and increased neocortical engagement during delayed retrieval. Additionally, we tested if this effect was modulated by individual differences in a cognitive proxy measure of baseline catecholamine synthesis capacity. METHODS: Fifty-three healthy males underwent a between-subjects, double-blind, placebo-controlled procedure across 2 days. On day 1, subjects studied and retrieved object-location associations and received 20 mg of methylphenidate or placebo. Drug intake was timed so that methylphenidate was expected to affect early consolidation but not encoding or retrieval. Memory was tested again while subjects were scanned three days later. RESULTS: Methylphenidate did not facilitate memory performance, and there was no significant group difference in activation during delayed retrieval. However, memory representations differed between groups depending on baseline catecholamines. The placebo group showed increased activation in occipito-temporal regions but decreased connectivity with the hippocampus, associated with lower baseline catecholamine synthesis capacity. The methylphenidate group showed stronger activation in the postcentral gyrus, associated with higher baseline catecholamine synthesis capacity. CONCLUSIONS: Altogether, methylphenidate during early consolidation did not foster long-term memory performance, but it affected retrieval-related neural processes depending on individual levels of baseline catecholamines

Prefrontal neuronal ensembles link prior knowledge with novel actions during flexible action selection

Summary: We make decisions based on currently perceivable information or an internal model of the environment. The medial prefrontal cortex (mPFC) and its interaction with the hippocampus have been implicated in the latter, model-based decision-making; however, the underlying computational properties remain incompletely understood. We have examined mPFC spiking and hippocampal oscillatory activity while rats flexibly select new actions using a known associative structure of environmental cues and outcomes. During action selection, the mPFC reinstates representations of the associative structure. These awake reactivation events are accompanied by synchronous firings among neurons coding the associative structure and those coding actions. Moreover, their functional coupling is strengthened upon the reactivation events leading to adaptive actions. In contrast, only cue-coding neurons improve functional coupling during hippocampal sharp wave ripples. Thus, the lack of direct experience disconnects the mPFC from the hippocampus to independently form self-organized neuronal ensemble dynamics linking prior knowledge with novel actions

Unilateral lateral entorhinal inactivation impairs memory expression in trace eyeblink conditioning

Memory in trace eyeblink conditioning is mediated by an inter-connected network that involves the hippocampus (HPC), several neocortical regions, and the cerebellum. This network reorganizes after learning as the center of the network shifts from the HPC to the medial prefrontal cortex (mPFC). Despite the network reorganization, the lateral entorhinal cortex (LEC) plays a stable role in expressing recently acquired HPC-dependent memory as well as remotely acquired mPFC-dependent memory. Entorhinal involvement in recent memory expression may be attributed to its previously proposed interactions with the HPC. In contrast, it remains unknown how the LEC participates in memory expression after the network disengages from the HPC. The present study tested the possibility that the LEC and mPFC functionally interact during remote memory expression by examining the impact of pharmacological inactivation of the LEC in one hemisphere and the mPFC in the contralateral hemisphere on memory expression in rats. Memory expression one day and one month after learning was significantly impaired after LEC-mPFC inactivation; however, the degree of impairment was comparable to that after unilateral LEC inactivation. Unilateral mPFC inactivation had no effect on recent or remote memory expression. These results suggest that the integrity of the LEC in both hemispheres is necessary for memory expression. Functional interactions between the LEC and mPFC should therefore be tested with an alternative design