Vestibular Modulation of Long-Term Potentiation and NMDA Receptor Expression in the Hippocampus.

Loss of vestibular function is known to cause spatial memory deficits and hippocampal dysfunction, in terms of impaired place cell firing and abnormal theta rhythm. Based on these results, it has been of interest to determine whether vestibular loss also affects the development and maintenance of long-term potentiation (LTP) in the hippocampus. This article summarizes and critically reviews the studies of hippocampal LTP following a vestibular loss and its relationship to NMDA receptor expression, that have been published to date. Although the available in vitro studies indicate that unilateral vestibular loss (UVL) results in reduced hippocampal field potentials in CA1 and the dentate gyrus (DG), the in vivo studies involving bilateral vestibular loss (BVL) do not. This may be due to the differences between UVL and BVL or it could be a result of in vitro/in vivo differences. One in vitro study reported a decrease in LTP in hippocampal slices following UVL; however, the two available in vivo studies have reported different results: either no effect or an increase in EPSP/Population Spike (ES) potentiation. This discrepancy may be due to the different high-frequency stimulation (HFS) paradigms used to induce LTP. The increased ES potentiation following BVL may be related to an increase in synaptic NMDA receptors, possibly increasing the flow of vestibular input coming into CA1, with a loss of selectivity. This might cause increased excitability and synaptic noise, which might lead to a degradation of spatial learning and memory.

Dorsal, but not ventral, hippocampal inactivation alters deliberation in rats.

When facing a choice at a decision point in a maze, rats often display hesitations, pauses and reorientations. Such "vicarious trial and error" (VTE) behavior is thought to reflect decision making about which choice option is best, and thus a deliberation process. Although deliberation relies on a wide neural network, the dorsal hippocampus appears to play a prominent role through both its neural activity and its dynamic interplay with other brain areas. In contrast, the involvement of the ventral hippocampus in deliberation is unexplored. Here, we compared directly the effects of dorsal (dHPC) and ventral intermediate (vHPC) hippocampal inactivations induced by intracerebral muscimol injections on VTE behavior as a model of deliberation. To this aim, we analyzed VTE events as rats were required to switch strategy to a new unlearned reward rule. We used a protocol in which task performance in muscimol-injected animals was minimally altered so as to evidence specific effects on VTE behavior. Our results show subtle alterations in VTE behavior following dHPC, but not vHPC, inactivations, therefore suggesting a specific contribution of the dorsal hippocampus to deliberation through its role in prospective evaluation of future actions.

Using MRI to predict the fate of excitotoxic lesions in rats.

Excitotoxic lesions are frequently used to assess the role of cerebral structures in cognitive processes in rodents. However, the precise site and extent of these lesions remain unknown without histological verifications. Using a 7-Teslas MRI system and a T2-weighted turbo-RARE sequence, MR images were acquired at several time points following NMDA lesions (1h, 6h, 24h, 48h, 1 week and 2 weeks). NMDA infusions into the parenchyma induced a clear and delineable hyperintense signal from 1h up to 1-week post-surgery. Hyperintensity volumes were compared with NeuN and Cresyl violet histological quantifications of the lesion magnitude. NMDA-induced hypersignal is observed as soon as 1h post-injection and is a reliable estimate of the presence (or absence) of a lesion. Compared to NeuN, Cresyl violet staining underestimates the extent of the lesion in significant proportions. The MRI hyperintensity generated by NMDA instillation into the parenchyma can be used as a powerful tool to confirm the diffusion of the drug into the cerebral tissue, to ascertain the locus of injection and predict with a high success rate the fate of NMDA lesions as soon as 1h post-surgery. This approach could be very useful in a large variety of lesion studies in rodents.

Ventral Midline Thalamus Is Necessary for Hippocampal Place Field Stability and Cell Firing Modulation.

The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip-mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields.SIGNIFICANCE STATEMENT Growing evidence suggest that the ventral midline thalamic nuclei (reuniens and rhomboid) might play a substantial role in various cognitive tasks including spatial memory. In the present article, we show that the lesions of these nuclei impair the spatial representations encoded by CA1 place cells of both familiar and novel environments. First, reduced variability of place cell firing appears to indicate an impairment of attentional processes. Second, impaired stability of place cell representations could explain the long-term memory deficits observed in previous behavioral studies.

Dynamic expression of the polysialyltransferase in adult rat hippocampus performing an olfactory associative task.

Neural cell adhesion molecule (NCAM) is associated with polysialic acid (PSA), and its function is highly dependent on the extent of polysialylation through the activity of two polysialyltransferases, sialyltransferase-X (STX) and polysialyltransferase (PST). PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. The involvement of STX and PST during mnesic processes was assessed in the adult rat hippocampus. We investigated whether different levels in learning and memory using an olfactory associative task influenced STX and PST gene expression in the hippocampus using semiquantitative transcription-polymerase chain reaction. Then, NCAM polysialylation and cell proliferation were quantified in the dentate gyrus of a "Learning and Memory" group using immunohistochemistry. We found that only the expression level of PST mRNA increased with learning performance and returned to an initial level when learned associations were consolidated in long-term memory, while STX mRNA levels remained unchanged. This phenomenon was accompanied by an increase in PSA on NCAM but not by cell proliferation in the dentate gyrus. Our results suggest a different involvement for STX and PST in neural plasticity: while STX is probably involved in the proliferation of neural progenitor cells, PST could play a key role in synaptic plasticity of mature neural networks. The expression of the STX and PST genes could, therefore, be useful markers of neurobiological plasticity in the brain, allowing to follow chronological events in limbic and cortical structures related first to learning and memory processes (for PST) and, second, to adult neurogenesis processes (for STX).

Differential role of the dorsal hippocampus, ventro-intermediate hippocampus, and medial prefrontal cortex in updating the value of a spatial goal.

Encoding of a goal with a specific value while performing a place navigation task involves the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC), and depends on the coordination between mPFC and the ventro-intermediate hippocampus (vHPC).The present work investigates the contribution of mPFC, dHPC, and vHPC when the rat has to update the value of a goal. Rats were trained to navigate to an uncued goal in order to release a food pellet in a continuous place navigation task. When they had reached criterion performance level in the task, they were subjected to a single "flash session" in which they were exposed to an aversive strobe light during goal visits instead of receiving a food reward. Just before the flash session, the GABA(A) agonist muscimol was injected to temporarily inactivate mPFC, dHPC, or vHPC. The ability to recall the changed value of the goal was tested on the next day. We first demonstrate the aversive effect of the strobe light by showing that rats learn to avoid the goal much more rapidly in the flash session than during a simple extinction session in which goal visits are not rewarded. Furthermore, while dHPC inactivation had no effect on learning and recalling the new goal value, vHPC muscimol injections considerably delayed goal value updating during the flash session, which resulted in a slight deficit during recall. In contrast, mPFC muscimol injections induced faster goal value updating but the rats were markedly impaired on recalling the new goal value on the next day. These results suggest that, contrary to mPFC and dHPC, vHPC is required for updating the value of a goal. In contrast, mPFC is necessary for long-term retention of this updating.

Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats.

Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of long-term potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggest that Kv4 channels could increase the signal-to-noise ratio during information acquisition, thereby allowing a better encoding of the memory trace.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory.

The tissue inhibitor of metalloproteinases-1 (TIMP-1) belongs to a family of multifunctional proteins that inhibit matrix metalloproteinases (MMPs), but also regulate cell growth, proliferation, migration and apoptosis in non-nervous tissues. We had previously reported that kainate (KA)-mediated excitotoxic seizures induce the expression of TIMP-1 in resistant neurons and reactive astrocytes of the rat CNS, but the functional implications of these changes had not been elucidated. In the present work we used a targeted gene null mutation in mice to investigate in vivo the involvement of TIMP-1 in neuronal death and axonal sprouting following KA. We found no differences in seizure behaviour between the wild-type (WT) and the TIMP-1 knock-out (KO) mice, without any compensation by other TIMPs, at least at the mRNA level. However, the TIMP-1 KO mice were resistant to excitotoxicity and did not undergo the typical mossy fibre sprouting observed in WT mice. The lack of TIMP-1 paradoxically hampered the increase in the activity of MMPs observed in the seizing WT mice. In addition, we demonstrate that learning and memory are impaired in untreated KO mice. In conclusion, this study provides the first in vivo evidence for the implication of TIMP-1 in neuronal death and axonal sprouting in a pathological situation, but also suggests the involvement of TIMP-1 in the synaptic mechanisms underlying learning and memory in physiological conditions. More generally, these data support the idea that the control of proteolysis is instrumental for pathological and physiological processes in the brain.

Olfactory associative discrimination: a model for studying modifications of synaptic efficacy in neuronal networks supporting long-term memory.

This review summarizes research that correlates behavioral performance and cellular physiology leading to modifications in the neuronal networks supporting long-term memory in the mammalian brain. Rats were trained in an olfactory associative discrimination task in which natural odors were replaced by mimetic olfactory stimulations. Olfactory learning induced synaptic modifications that affected behavioral performance along the central olfactory pathways. Starting with an early increase in monosynaptic efficacy in the dentate gyrus on the first session, a polysynaptic modification appeared later on in this hippocampal network, when rats began to make associations between cues and rewards. Therefore, only when rats made consistent associations did a long-term potentiation in the synapses of the piriform cortex pyramidal neurons appear. These modifications may correspond to the long-term storage of the meaning of the cue-reward association in a specific cortical area. Based on these cumulative results, a hypothesis is proposed to account for how, when, and where synaptic modifications in neural networks are required to constitute long-term memory.