Ventral striatum regulates behavioral response to ethanol and MDMA combination.

Our previous studies consistently showed that MDMA-induced locomotor hyperactivity is dramatically increased by coadministration of ethanol (EtOH) in rats, indicating possible potentiation of MDMA abuse liability. Thus, we aimed to identify the brain region(s) and neuropharmacological substrates involved in the pharmacodynamics of this potentiation. We first showed that potentiation of locomotor activity by the combination of ip administration of EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) is delay sensitive and maximal when both drugs are injected simultaneously. Then, we used the 2-deoxyglucose quantitative autoradiography technique to assess the impact of EtOH, MDMA, or their combination on local cerebral metabolic rates for glucose (CMRglcs). We showed a specific metabolic activation in the ventral striatum (VS) under MDMA + EtOH versus MDMA or EtOH alone. We next tested if reversible (tetrodotoxin, TTX) or permanent (6-hydrodoxyopamine, 6-OHDA) lesion of the VS could affect locomotor response to MDMA and MDMA + EtOH. Finally, we blocked dopamine D1 or glutamate NMDA receptors in the VS and measured the effects of MDMA and MDMA + EtOH on locomotor activity. We showed that bilateral reversible inactivation (TTX) or permanent lesion (6-OHDA) of the VS prevented the potentiation by EtOH of MDMA-induced locomotor hyperactivity. Likewise, blockade of D1 or NMDA receptors in the VS also reduced the potentiation of MDMA locomotor activity by EtOH. These data indicate that dopamine D1 and glutamate NMDA receptor-driven mechanisms in the VS play a key role in the pharmacodynamics of EtOH-induced potentiation of the locomotor effects of MDMA.

Shifting between response and place strategies in maze navigation: Effects of training, cue availability and functional inactivation of striatum or hippocampus in rats.

Response and place memory systems have long been considered independent, encoding information in parallel, and involving the striatum and hippocampus, respectively. Most experimental studies supporting this view used simple, repetitive tasks, with unrestrained access to spatial cues. They did not give animals an opportunity to correct a response strategy by shifting to a place one, which would demonstrate dynamic, adaptive interactions between both memory systems in the navigation correction process. In a first experiment, rats were trained in the double-H maze for different durations (1, 6, or 14 days; 4 trials/day) to acquire a repetitive task in darkness (forcing a response memory-based strategy) or normal light (placing response and place memory systems in balance), or to acquire a place memory. All rats were given a misleading shifted-start probe trial 24-h post-training to test both their strategy and their ability to correct their navigation directly or in response to negative feedback. Additional analyses focused on the dorsal striatum and the dorsal hippocampus using c-Fos gene expression imaging and, in a second experiment, reversible muscimol inactivation. The results indicate that, depending on training protocol and duration, the striatum, which was unexpectedly the first to come into play in the dual strategy task, and the hippocampus are both required when rats have to correct their navigation after having acquired a repetitive task in a cued environment. Partly contradicting the model established by Packard and McGaugh (1996, Neurobiology of Learning and Memory, vol. 65), these data point to memory systems that interact in more complex ways than considered so far. To some extent, they also challenge the notion of hippocampus-independent response memory and striatum-independent place memory systems.

Environmental enrichment enhances systems-level consolidation of a spatial memory after lesions of the ventral midline thalamus.

Lesions of the reuniens and rhomboid (ReRh) thalamic nuclei in rats do not alter spatial learning but shorten the period of memory persistence (Loureiro et al. 2012). Such persistence requires a hippocampo-cortical (prefrontal) dialog leading to memory consolidation at the systems level. Evidence for reciprocal connections with the hippocampus and the medial prefrontal cortex (mPFC) makes the ReRh a potential hub for regulating hippocampo-cortical interactions. As environmental enrichment (EE) fosters recovery of declarative-like memory functions after diencephalic lesions (e.g., anterior thalamus), we studied the possibility of triggering recovery of systems-level consolidation in ReRh lesioned rats using a 40-day postsurgical EE. Remote memory was tested 25days post-acquisition in a Morris water maze. The functional activity associated with retrieval was quantified using c-Fos imaging in the dorsal hippocampus, mPFC, intralaminar thalamic nuclei, and amygdala. EE enhanced remote memory in ReRh rats. Conversely, ReRh rats housed in standard conditions were impaired. C-Fos immunohistochemistry showed a higher recruitment of the mPFC in enriched vs. standard rats with ReRh lesions during retrieval. ReRh rats raised in standard conditions showed weaker c-Fos expression than their sham-operated counterparts. The reinstatement of memory capacity implicated an EE-triggered modification of functional connectivity: EE reduced a marked lesion-induced increase in baseline c-Fos expression in the amygdala. Thus, enriched housing conditions counteracted the negative impact of ReRh lesions on spatial memory persistence. These effects could be the EE-triggered consequence of an enhanced neuronal activation in the mPFC, along with an attenuation of a lesion-induced hyperactivity in the amygdala.

The ventral midline thalamus contributes to strategy shifting in a memory task requiring both prefrontal cortical and hippocampal functions.

Electrophysiological and neuroanatomical evidence for reciprocal connections with the medial prefrontal cortex (mPFC) and the hippocampus make the reuniens and rhomboid (ReRh) thalamic nuclei a putatively major functional link for regulations of cortico-hippocampal interactions. In a first experiment using a new water escape device for rodents, the double-H maze, we demonstrated in rats that a bilateral muscimol (MSCI) inactivation (0.70 vs 0.26 and 0 nmol) of the mPFC or dorsal hippocampus (dHip) induces major deficits in a strategy shifting/spatial memory retrieval task. By way of comparison, only dHip inactivation impaired recall in a classical spatial memory task in the Morris water maze. In the second experiment, we showed that ReRh inactivation using 0.70 nmol of MSCI, which reduced performance without obliterating memory retrieval in the water maze, produces an as large strategy shifting/memory retrieval deficit as mPFC or dHip inactivation in the double-H maze. Thus, behavioral adaptations to task contingency modifications requiring a shift toward the use of a memory for place might operate in a distributed circuit encompassing the mPFC (as the potential set-shifting structure), the hippocampus (as the spatial memory substrate), and the ventral midline thalamus, and therein the ReRh (as the coordinator of this processing). The results of the current experiments provide a significant extension of our understanding of the involvement of ventral midline thalamic nuclei in cognitive processes: they point to a role of the ReRh in strategy shifting in a memory task requiring cortical and hippocampal functions and further elucidate the functional system underlying behavioral flexibility.

In relentless pursuit of the white whale: A role for the ventral midline thalamus in behavioral flexibility and adaption?

The reuniens (Re) nucleus is located in the ventral midline thalamus. It has fostered increasing interest, not only for its participation in a variety of cognitive functions (e.g., spatial working memory, systemic consolidation, reconsolidation, extinction of fear or generalization), but also for its neuroanatomical positioning as a bidirectional relay between the prefrontal cortex (PFC) and the hippocampus (HIP). In this review we compile and discuss recent studies having tackled a possible implication of the Re nucleus in behavioral flexibility, a major PFC-dependent executive function controlling goal-directed behaviors. Experiments considered explored a possible role for the Re nucleus in perseveration, reversal learning, fear extinction, and set-shifting. They point to a contribution of this nucleus to behavioral flexibility, mainly by its connections with the PFC, but possibly also by those with the hippocampus, and even with the amygdala, at least for fear-related behavior. As such, the Re nucleus could be a crucial crossroad supporting a PFC-orchestrated ability to cope with new, potentially unpredictable environmental contingencies, and thus behavioral flexibility and adaption.

The ventral midline thalamus (reuniens and rhomboid nuclei) contributes to the persistence of spatial memory in rats.

The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: >500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks.

Inhibition of the ventral midline thalamus does not alter encoding, short-term holding or retrieval of spatial information in rats performing a water-escape working memory task.

Working memory (WM) is a function operating in three successive phases: encoding (sample trial), holding (delay), and retrieval (test trial) of information. Studies point to a possible implication of the thalamic reuniens nucleus (Re) in spatial WM (SWM). In which of the aforementioned 3 phases the Re has a function is largely unknown. Recently, in a delayed SWM water-escape task, we found that performance during the retrieval trial correlated positively with c-Fos expression in the Re nucleus, suggesting participation in retrieval. Here, we used the same task and muscimol (MUSC) inhibition or DREADD(hM4Di)-mediated inhibition of the Re during information encoding, right thereafter (thereby affecting the holding phase), or during the retrieval trial. A 6-hour delay separated encoding from retrieval. Concerning SWM, MUSC in the Re nucleus did not alter performance, be it during or after encoding, or during evaluation. CNO administered before encoding in DREADD-expressing rats was also ineffective, although CNO-induced inhibition disrupted set shifting performance, as found previously (Quet et al., Brain Struct Function 225, 2020), thereby validating DREADD efficiency. These findings are the first that do not support an implication of the Re nucleus in SWM. As most previous studies used T-maze alternation tasks, which carry high proactive interference risks, an important question to resolve now is whether the Re nucleus is required in (T-maze alternation) tasks using very short information-holding delays (seconds to minutes), and less so in other short-term spatial memory tasks with longer information holding intervals (hours) and therefore reduced interference risks.

Altered activity-regulated H3K9 acetylation at TGF-beta signaling genes during egocentric memory in Huntington's disease.

Molecular mechanisms underlying cognitive deficits in Huntington's disease (HD), a striatal neurodegenerative disorder, are unknown. Here, we generated ChIPseq, 4Cseq and RNAseq data on striatal tissue of HD and control mice during striatum-dependent egocentric memory process. Multi-omics analyses showed altered activity-dependent epigenetic gene reprogramming of neuronal and glial genes regulating striatal plasticity in HD mice, which correlated with memory deficit. First, our data reveal that spatial chromatin re-organization and transcriptional induction of BDNF-related markers, regulating neuronal plasticity, were reduced since memory acquisition in the striatum of HD mice. Second, our data show that epigenetic memory implicating H3K9 acetylation, which established during late phase of memory process (e.g. during consolidation/recall) and contributed to glia-mediated, TGFß-dependent plasticity, was compromised in HD mouse striatum. Specifically, memory-dependent regulation of H3K9 acetylation was impaired at genes controlling extracellular matrix and myelination. Our study investigating the interplay between epigenetics and memory identifies H3K9 acetylation and TGFß signaling as new targets of striatal plasticity, which might offer innovative leads to improve HD.

Routes of the thalamus through the history of neuroanatomy.

The most distant roots of neuroanatomy trace back to antiquity, with the first human dissections, but no document which would identify the thalamus as a brain structure has reached us. Claudius Galenus (Galen) gave to the thalamus the name 'thalamus nervorum opticorum', but later on, other names were used (e.g., anchae, or buttocks-like). In 1543, Andreas Vesalius provided the first quality illustrations of the thalamus. During the 19th century, tissue staining techniques and ablative studies contributed to the breakdown of the thalamus into subregions and nuclei. The next step was taken using radiomarkers to identify connections in the absence of lesions. Anterograde and retrograde tracing methods arose in the late 1960s, supporting extension, revision, or confirmation of previously established knowledge. The use of the first viral tracers introduced a new methodological breakthrough in the mid-1970s. Another important step was supported by advances in neuroimaging of the thalamus in the 21th century. The current review follows the history of the thalamus through these technical revolutions from Antiquity to the present day.

The nucleus reuniens, a thalamic relay for cortico-hippocampal interaction in recent and remote memory consolidation.

The consolidation of declarative memories is believed to occur mostly during sleep and involves a dialogue between two brain regions, the hippocampus and the medial prefrontal cortex. The information encoded during experience by neuronal assemblies is replayed during sleep leading to the progressive strengthening and integration of the memory trace in the prefrontal cortex. The gradual transfer of information from the hippocampus to the medial prefrontal cortex for long-term storage requires the synchronization of cortico-hippocampal networks by different oscillations, like ripples, spindles, and slow oscillations. Recent studies suggest the involvement of a third partner, the nucleus reuniens, in memory consolidation. Its bidirectional connections with the hippocampus and medial prefrontal cortex place the reuniens in a key position to relay information between the two structures. Indeed, many topical works reveal the original role that the nucleus reuniens occupies in different recent and remote memories consolidation. This review aimed to examine these contributions, as well as its functional embedment in this complex memory network, and provide some insights on the possible mechanisms.

The reuniens and rhomboid nuclei of the thalamus: A crossroads for cognition-relevant information processing?

Over the past twenty years, the reuniens and rhomboid (ReRh) nuclei, which constitute the ventral midline thalamus, have received constantly growing attention. Since our first review article about the functional contributions of ReRh nuclei (Cassel et al., 2013), numerous (>80) important papers have extended anatomical knowledge, including at a developmental level, introduced new and very original electrophysiological insights on ReRh functions, and brought novel results on cognitive and non-cognitive implications of the ReRh. The current review will cover these recent articles, more on Re than on Rh, and their contribution will be approached according to their affiliation with work before 2013. These neuroanatomical, electrophysiological or behavioral findings appear coherent and point to the ReRh nuclei as two major components of a multistructural system supporting numerous cognitive (and non-cognitive) functions. They gate the flow of information, perhaps especially from the medial prefrontal cortex to the hippocampus and back, and coordinate activity and processing across these two (and possibly other) brain regions of major cognitive relevance.

Ventral midline thalamus is not necessary for systemic consolidation of a social memory in the rat.

According to the standard theory of memory consolidation, recent memories are stored in the hippocampus before their transfer to cortical modules, a process called systemic consolidation. The ventral midline thalamus (reuniens and rhomboid nuclei, ReRh) takes part in this transfer as its lesion disrupts systemic consolidation of spatial and contextual fear memories. Here, we wondered whether ReRh lesions would also affect the systemic consolidation of another type of memory, namely an olfaction-based social memory. To address this question we focused on social transmission of food preference. Adult Long-Evans rats were subjected to N-methyl-d-aspartate-induced, fibre-sparing lesions of the ReRh nuclei or to a sham-operation, and subsequently trained in a social transmission of food preference paradigm. Retrieval was tested on the next day (recent memory, nSham = 10, nReRh = 12) or after a 25-day delay (remote memory, nSham = 10, nReRh = 10). All rats, whether sham-operated or subjected to ReRh lesions, learned and remembered the task normally, whatever the delay. Compared to our former results on spatial and contextual fear memories (Ali et al., 2017; Klein et al., 2019; Loureiro et al., 2012; Quet et al., 2020), the present findings indicate that the ReRh nuclei might not be part of a generic, systemic consolidation mechanism processing all kinds of memories in order to make them persistent. The difference between social transmission of food preference and spatial or contextual fear memories could be explained by the fact that social transmission of food preference is not hippocampus-dependent and that the persistence of social transmission of food preference memory relies on different circuits.

The reuniens and rhomboid nuclei are necessary for contextual fear memory persistence in rats.

Memory persistence refers to the process by which a temporary, labile memory is transformed into a stable and long-lasting state. This process involves a reorganization of brain networks at systems level, which requires functional interactions between the hippocampus (HP) and medial prefrontal cortex (mPFC). The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are bidirectionally connected with both regions, and we previously demonstrated their crucial role in spatial memory persistence. We now investigated, in male rats, whether specific manipulations of ReRh activity also affected contextual and cued fear memory persistence. We showed that the permanent ReRh lesion impaired remote, but not recent contextual fear memory. Tone-cued recent and remote fear memory were spared by the lesion. In intact rats, acute chemogenetic ReRh inhibition conducted before recall of either recent or remote contextual fear memories produced no effect, indicating that the ReRh nuclei are not required for retrieval of such memories. This was also suggested by a functional cellular imaging approach, as retrieval did not alter c-fos expression in the ReRh. Collectively, these data are compatible with a role for the ReRh in 'off-line' consolidation of a contextual fear memory and support the crucial importance of ventral midline thalamic nuclei in systems consolidation of memories.

Hippocampal-dependent spatial memory functions might be lateralized in rats: An approach combining gene expression profiling and reversible inactivation.

The hippocampus is involved in spatial memory processes, as established in a variety of species such as birds and mammals including humans. In humans, some hippocampal-dependent memory functions may be lateralized, the right hippocampus being predominantly involved in spatial navigation. In rodents, the question of possible lateralization remains open. Therefore, we first microdissected the CA1 subregion of the left and right dorsal hippocampi for analysis of mRNA expression using microarrays in rats having learnt a reference memory task in the Morris water-maze. Relative to untrained controls, 623 genes were differentially expressed in the right hippocampus, against only 74 in the left hippocampus, in the rats that had learnt the hidden platform location. Thus, in the right hippocampus, 299 genes were induced, 324 were repressed, and about half of them participate in signaling and transport, metabolism, and nervous system functions. In addition, most differentially expressed genes associated with spatial learning have been previously related to synaptic plasticity and memory. We then subjected rats to unilateral (left or right) or bilateral reversible functional inactivations in the dorsal hippocampus; lidocaine was infused either before each acquisition session or before retrieval of a reference spatial memory in the Morris water maze. We found that after drug-free acquisition, right or bilateral lidocaine inactivation (vs. left, or bilateral phosphate buffered saline (PBS) infusions) of the dorsal hippocampus just before a delayed (24 h) probe trial impaired performance. Conversely, left or bilateral hippocampus inactivation (vs. right, or bilateral PBS infusions) before each acquisition session weakened performance during a delayed, drug-free probe trial. Our data confirm a functional association between transcriptional activity within the dorsal hippocampus and spatial memory in the rat. Further, they suggest that there could be a leftward bias of hippocampal functions in engram formation or information transfer, and a rightward bias in spatial memory storage/retrieval processes.

Ventral midline thalamus lesion prevents persistence of new (learning-triggered) hippocampal spines, delayed neocortical spinogenesis, and spatial memory durability.

The ventral midline thalamus contributes to hippocampo-cortical interactions supporting systems-level consolidation of memories. Recent hippocampus-dependent memories rely on hippocampal connectivity remodeling. Remote memories are underpinned by neocortical connectivity remodeling. After a ventral midline thalamus lesion, recent spatial memories are formed normally but do not last. Why these memories do not endure after the lesion is unknown. We hypothesized that a lesion could interfere with hippocampal and/or neocortical connectivity remodeling. To test this hypothesis, in a first experiment male rats were subjected to lesion of the reuniens and rhomboid (ReRh) nuclei, trained in a water maze, and tested in a probe trial 5 or 25 days post-acquisition. Dendritic spines were counted in the dorsal hippocampus and medial prefrontal cortex. Spatial learning resulted in a significant increase of mushroom spines in region CA1. This modification persisted between 5 and 25 days post-acquisition in Sham rats, not in rats with ReRh lesion. Furthermore, 25 days after acquisition, the number of mushroom spines in the anterior cingulate cortex (ACC) had undergone a dramatic increase in Sham rats; ReRh lesion prevented this gain. In a second experiment, the increase of c-Fos expression in CA1 accompanying memory retrieval was not affected by the lesion, be it for recent or remote memory. However, in the ACC, the lesion had reduced the retrieval-triggered c-Fos expression observed 25 days post-acquisition. These observations suggest that a ReRh lesion might disrupt spatial remote memory formation by preventing persistence of early remodeled hippocampal connectivity, and spinogenesis in the ACC.

A Miniaturized, Programmable Deep-Brain Stimulator for Group-Housing and Water Maze Use.

Pre-clinical deep-brain stimulation (DBS) research has observed a growing interest in the use of portable stimulation devices that can be carried by animals. Not only can such devices overcome many issues inherent with a cable tether, such as twisting or snagging, they can also be utilized in a greater variety of arenas, including enclosed or large mazes. However, these devices are not inherently designed for water-maze environments, and their use has been restricted to individually-housed rats in order to avoid damage from various social activities such as grooming, playing, or fighting. By taking advantage of 3D-printing techniques, this study demonstrates an ultra-small portable stimulator with an environmentally-protective device housing, that is suitable for both social-housing and water-maze environments. The miniature device offers 2 channels of charge-balanced biphasic pulses with a high compliance voltage (12 V), a magnetic switch, and a diverse range of programmable stimulus parameters and pulse modes. The device's capabilities have been verified in both chronic pair-housing and water-maze experiments that asses the effects of nucleus reuniens DBS. Theta-burst stimulation delivered during a reference-memory water-maze task (but not before) had induced performance deficits during both the acquisition and probe trials of a reference memory task. The results highlight a successful application of 3D-printing for expanding on the range of measurement modalities capable in DBS research.

Neurochemical Changes and c-Fos Mapping in the Brain after Carisbamate Treatment of Rats Subjected to Lithium-Pilocarpine-Induced Status Epilepticus.

The administration of lithium-pilocarpine (LiPilo) in adult rats is a validated model reproducing the main clinical and neuropathological features of temporal lobe epilepsy (TLE). Previous studies have shown that carisbamate (CRS) has the property of modifying epileptogenesis in this model. When treated with CRS, about 50% of rats undergoing LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of convulsive ones (commonly observed in TLE). The goal of this work was to determine some of the early changes that occur after CRS administration, as they could be involved in the insult- and epileptogenesis-modifying effects of CRS. Thus, we performed high-performance liquid chromatography (HPLC) to quantify levels of amino acids and monoamines, and c-Fos immunohistochemical labeling to map cerebral activation during seizures. Comparing rats treated one hour after SE onset with saline (CT), CRS, or diazepam (DZP), HPLC showed that 4 h after SE onset, dopamine (DA), norepinephrine (NE), and GABA levels were normal, whereas serotonin levels were increased. Using c-Fos labeling, we demonstrated increased activity in thalamic mediodorsal (MD) and laterodorsal (LD) nuclei in rats treated with CRS. In summary, at early times, CRS seems to modulate excitability by acting on some monoamine levels and increasing activity of MD and LD thalamic nuclei, suggesting a possible involvement of these nuclei in insult- and/or epileptogenesis-modifying effects of CRS.

The nonspecific thalamus: A place in a wedding bed for making memories last?

We summarize anatomical, electrophysiological and behavioral evidence that the rostral intralaminar (ILN) and the reuniens and rhomboid (ReRh) nuclei that belong to the nonspecific thalamus, might be part of a hippocampo-cortico-thalamic network underlying consolidation of enduring declarative(-like) memories at systems level. The first part of this review describes the anatomical and functional organization of these thalamic nuclei. The second part presents the theoretical models supporting the active systems-level consolidation, a process that relies upon sleep specific field-potential oscillations occurring during both slow-wave sleep (SWS) and rapid eye movement (REM) sleep. The last part presents data in the rat showing that the lesion of the rostral ILN or of the ReRh specifically hinders the formation of remote spatial memories without affecting task acquisition or retrieval of a recent memory. These results showing a critical role of the ILN and ReRh nuclei in the transformation of a recent memory into a remote one are discussed in the context of their control of cortical arousal (ARAS) and of thalamo-cortico-thalamic synchronization.

Importance of the ventral midline thalamus in driving hippocampal functions.

The ventral midline of the thalamus encompasses the reuniens and rhomboid (ReRh) nuclei. These nuclei are bidirectionally connected with the hippocampus and the medial prefrontal cortex (mPFC). About 8% of the neurons of the Re have collaterals in both structures. The ReRh nuclei provide the major thalamic input to the hippocampus. Their stimulation induces long-term potentiation in region CA1, suggesting a role in hippocampal plasticity. Experimental manipulations of the ReRh nuclei such as lesions, reversible inactivations, or optogenetic stimulations produce alterations of cognitive functions, especially in tasks known for their sensitivity to lesions of the hippocampus, but also of the mPFC. Behavioral approaches suggest that the ReRh nuclei might relay incoming signals from the mPFC both to the hippocampus and back to the mPFC. Thus, the Re and Rh nuclei have a role in orchestrating the information flow between the hippocampus and the mPFC, and this orchestration has both "online" and "off-line" implications in cognitive functions.

Local cerebral blood flow during lithium-pilocarpine seizures in the developing and adult rat: role of coupling between blood flow and metabolism in the genesis of neuronal damage.

Coupling between local cerebral blood flow and local cerebral metabolic rate for glucose is involved in the pathogenesis of epilepsy-related neuronal damage in the adult brain; however, its role in the immature brain is unknown. Lithium-pilocarpine-induced status epilepticus is associated with extended damage in adult rats, mostly in the forebrain limbic areas and thalamus, whereas damage was moderate in 21-day-old rats (P21) or absent in P10 rats. The quantitative autoradiographic [14C]iodoantipyrine technique was applied to measure the consequences of lithium-pilocarpine status epilepticus on local cerebral blood flow. In adult and P21 rats, local cerebral blood flow rates increased by 50% to 400%; the highest increases were recorded in regions showing damage in adults. At P10, local cerebral blood flow rates decreased by 40% to 60% in most areas, except in some forebrain regions showing no change during status epilepticus. In areas injured when status epilepticus was induced in adults, a strong hypermetabolism (Fernandes et al., 1999) not matched by comparable local cerebral blood flow increases was present in rats of all ages, whereas in damage-resistant areas, local cerebral metabolic rate for glucose and local cerebral blood flow remained coupled in the three age groups. Thus, the level of coupling between blood flow supply and metabolism is not involved in seizure-related brain damage in the developing brain, which appears to be resistant to the consequences of such a mismatch.