Alteration of Lateral Habenula Function Prevents the Proper Exploration of a Novel Environment.

The lateral habenula (LHb) is an epithalamic brain region viewed as a converging hub, integrating information from a large connectome and then projecting to few critical midbrain monoaminergic systems. Numerous studies have explored the roles of the LHb, notably in aversion and avoidance. An important recurring finding when manipulating the LHb is the induction of anxiety-related behaviours. However, its exact role in such behaviours remains poorly understood. In the present study, we used two pharmacological approaches altering LHb activity, intra-LHb infusion of either the GABA-A receptor agonist, Muscimol, or the glutamatergic AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and exposed rats to three consecutive open field (OF) sessions. We found that both pharmacological treatments prevented rats to explore the centre of the OF, considered as the most anxiogenic part of the apparatus, across the three OF sessions. In addition, during the first, but not the two consecutive sessions, both treatments prevented a thorough exploration of the OF. Altogether, these results confirm the crucial role played by the LHb in anxiety-related behaviours and further suggest its implication in the exploration of new anxiogenic environments.

Functional brain-wide network mapping during acute stress exposure in rats: Interaction between the lateral habenula and cortical, amygdalar, hypothalamic and monoaminergic regions.

Upon stress exposure, a broad network of structures comes into play in order to provide adequate responses and restore homeostasis. It has been known for decades that the main structures engaged during the stress response are the medial prefrontal cortex, the amygdala, the hippocampus, the hypothalamus, the monoaminergic systems (noradrenaline, dopamine and serotonin) and the periaqueductal gray. The lateral habenula (LHb) is an epithalamic structure directly connected to prefrontal cortical areas and to the amygdala, whereas it functionally interacts with the hippocampus. Also, it is a main modulator of monoaminergic systems. The LHb is activated upon exposure to basically all types of stressors, suggesting it is also involved in the stress response. However, it remains unknown if and how the LHb functionally interacts with the broad stress response network. In the current study we performed in rats a restraint stress procedure followed by immunohistochemical staining of the c-Fos protein throughout the brain. Using graph theory-based functional connectivity analyses, we confirm the principal hubs of the stress network (e.g., prefrontal cortex, amygdala and periventricular hypothalamus) and show that the LHb is engaged during stress exposure in close interaction with the medial prefrontal cortex, the lateral septum and the medial habenula. In addition, we performed DREADD-induced LHb inactivation during the same restraint paradigm in order to explore its consequences on the stress response network. This last experiment gave contrasting results as the DREADD ligand alone, clozapine-N-oxide, was able to modify the network.

Slow Wave Sleep Deficits in the Flinders Sensitive Line Rodent Model of Depression: Effects of Medial Forebrain Bundle Deep-Brain Stimulation.

Major Depressive Disorder (MDD) is an affective disorder typically accompanied by sleep disturbances. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) is an emerging intervention for treatment-resistant depression, but its effect on sleep has not been closely examined. Here we aimed to characterise sleep deficits in the Flinders sensitive line, an established rodent model of depression, and investigate the consequences of MFB stimulation on sleep-related phenotypes. Rats were implanted with bilateral stimulation electrodes in the MFB, surface electrodes to record electrocorticography and electromyography for sleep scoring and electrodes within the prelimbic cortex, nucleus accumbens (NAc) and dorsal hippocampus. Recordings of sleep and oscillatory activity were conducted prior to and following twenty-four hours of MFB stimulation. Behavioural anti-depressant effects were monitored using the forced swim test. Previously unreported abnormalities in the Flinders sensitive line rats were observed during slow wave sleep, including decreased circadian amplitude of its rhythm, a reduction in slow wave activity and elevated gamma band oscillations. Previously established rapid eye movement sleep deficits were replicated. MFB stimulation had anti-depressant effects on behavioural phenotype, but did not significantly impact sleep architecture; it suppressed elevated gamma activity during slow wave sleep in the electrocorticogram and prelimbic cortex signals. Diverse abnormalities in Flinders sensitive line rats emphasise slow wave sleep as a state of dysfunction in affective disorders. MFB stimulation is able to affect behaviour and sleep physiology without influencing sleep architecture. Gamma modulation may represent a component of antidepressant mechanism.

Lateral Habenula Beyond Avoidance: Roles in Stress, Memory, and Decision-Making With Implications for Psychiatric Disorders.

In this Perspective review, we highlight some of the less explored aspects of lateral habenula (LHb) function in contextual memory, sleep, and behavioral flexibility. We provide evidence that LHb is well-situated to integrate different internal state and multimodal sensory information from memory-, stress-, motivational-, and reward-related circuits essential for both survival and decision making. We further discuss the impact of early life stress (ELS) on LHb function as an example of stress-induced hyperactivity and dysregulation of neuromodulatory systems within the LHb that promote anhedonia and motivational deficits following ELS. We acknowledge that recent technological advancements in manipulation and recording of neural circuits in simplified and well-controlled behavioral paradigms have been invaluable in our understanding of the critical role of LHb in motivation and emotional regulation as well as the involvement of LHb dysfunction in stress-induced psychopathology. However, we also argue that the use of ethologically-relevant behaviors with consideration of complex aspects of decision-making is warranted for future studies of LHb contributions in a wide range of psychiatric illnesses. We conclude this Perspective with some of the outstanding issues for the field to consider where a multi-systems approach is needed to investigate the complex nature of LHb circuitry interactions with environmental stimuli that predisposes psychiatric disorders.

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.

Involvement of the lateral habenula in fear memory.

Increasing evidence points to the engagement of the lateral habenula (LHb) in the selection of appropriate behavioral responses in aversive situations. However, very few data have been gathered with respect to its role in fear memory formation, especially in learning paradigms in which brain areas involved in cognitive processes like the hippocampus (HPC) and the medial prefrontal cortex (mPFC) are required. A paradigm of this sort is trace fear conditioning, in which an aversive event is preceded by a discrete stimulus, generally a tone, but without the close temporal contiguity allowing for their association based on amygdala-dependent information processing. In a first experiment, we analyzed cellular activations (c-Fos expression) induced by trace fear conditioning in subregions of the habenular complex, HPC, mPFC and amygdala using a factorial analysis to unravel functional networks through correlational analysis of data. This analysis suggested that distinct LHb subregions engaged in different aspects of conditioning, e.g. associative processes and onset of fear responses. In a second experiment, we performed chemogenetic LHb inactivation during the conditioning phase of the trace fear conditioning paradigm and subsequently assessed contextual and tone fear memories. Whereas LHb inactivation did not modify rat's behavior during conditioning, it induced contextual memory deficits and enhanced fear to the tone. These results demonstrate the involvement of the LHb in fear memory. They further suggest that the LHb is engaged in learning about threatening environments through the selection of relevant information predictive of a danger.

The lateral habenula interacts with the hypothalamo-pituitary adrenal axis response upon stressful cognitive demand in rats.

The lateral habenula (LHb) is involved in emotional and cognitive behaviors. Recently, we have shown in rats that blockade of excitatory inputs to the LHb not only induced deficits of memory retrieval in the water maze, but also altered swim strategies (i.e., induced excessive thigmotaxis). The latter observation, although consistent with the occurrence of memory deficits, could also possibly be the consequence of an excessive level of stress, further suggesting a role for the LHb in the stress response in our behavioral paradigm. To test this hypothesis we performed in rats intra-LHb infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 267 ng/side in 0.3 µL), or vehicle, and assessed the responsiveness of the hypothalamo-pituitary adrenal (HPA) axis to environmental stressful or non-stressful situations. We have measured plasma corticosterone (CORT) concentrations at different time points before and following intra-LHb infusion of CNQX - or of the same volume of vehicle - in three conditions: during the probe test of a water maze experiment; in an anxiety test, the elevated plus maze; and in a home cage condition. Whereas there were no differences in the home cage condition and in the elevated plus maze, in the water maze experiment we observed that CNQX-treated rats presented, along with memory deficits, a higher level of blood CORT than vehicle-treated rats. These results suggest that perturbations of the modulation of the HPA axis are consecutive to the alteration of LHb function, whether it is the result of a defective direct control of the LHb over the HPA axis, or the consequence of memory deficits.

Role of the lateral habenula in memory through online processing of information.

Our memory abilities, whether they involve short-term working memory or long-term episodic or procedural memories, are essential for our well-being, our capacity to adapt to constraints of our environment and survival. Therefore, several key brain regions and neurotransmitter systems are engaged in the processing of sensory information to either maintain such information in working memory so that it will quickly be used, and/or participate in the elaboration and storage of enduring traces useful for longer periods of time. Animal research has recently attracted attention on the lateral habenula which, as shown in rodents and non-human primates, seems to process information stemming in the main regions involved in memory processing, e.g., the medial prefrontal cortex, the hippocampus, the amygdala, the septal region, the basal ganglia, and participates in the control of key memory-related neurotransmitters systems, i.e., dopamine, serotonin, acetylcholine. Recently, the lateral habenula has been involved in working and spatial reference memories, in rodents, likely by participating in online processing of contextual information. In addition, several behavioral studies strongly suggest that it is also involved in the processing of the emotional valance of incoming information in order to adapt to particularly stressful situations. Therefore, the lateral habenula appears like a key region at the interface between cognition and emotion to participate in the selection of appropriate behaviors.

The Lateral Habenula as a Relay of Cortical Information to Process Working Memory.

Working memory is a cognitive ability allowing the temporary storage of information to solve problems or adjust behavior. While working memory is known to mainly depend on the medial prefrontal cortex (mPFC), very few is known about how cortical information are relayed subcortically. By its connectivity, the lateral habenula (lHb) might act as a subcortical relay for cortical information. Indeed, the lHb receives inputs from several mPFC subregions, and recent findings suggest a role for the lHb in online processing of spatial information, a fundamental aspect of working memory. In rats, in a delayed non-matching to position paradigm, using focal microinjections of the GABAA agonist muscimol we showed that inactivation of the lHb (16 ng in 0.2 µL per side), as well as disconnection between the prelimbic region of the mPFC (mPFC/PrL, 32 ng in 0.4 µL in one hemisphere) and the lHb (16 ng in 0.2 µL in the lHb in the contralateral hemisphere) impaired working memory. The deficits were unlikely to result from motivational or motor deficits as muscimol did not affect reward collection or cue responding latencies, and did not increase the number of omissions. These results show for the first time the implication of the lHb in mPFC-dependent memory processes, likely as a relay of mPFC/PrL information. They also open new perspectives in the understanding of the top-down processing of high-level cognitive functions.

Excitatory Transmission to the Lateral Habenula Is Critical for Encoding and Retrieval of Spatial Memory.

The lateral habenula (LHb) is viewed as a relay between the limbic system, the basal ganglia (BG), and monoaminergic neurons of the midbrain. If a prominent role has been evidenced in BG-mediated functions such as value-based decision-making, very little is known about the involvement of the LHb in limbic functions such as memory processing. In the present study, we used two pharmacological approaches-LHb reversible inactivation with intra-LHb infusion of muscimol, an agonist of the GABA-A receptor, or blockade of excitatory inputs with intra-LHb infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the glutamatergic AMPA receptor-to investigate the involvement of the LHb in encoding, consolidation, and retrieval of spatial memory in the water maze (WM) in rats. We found that intra-LHb infusion of muscimol or CNQX prevented encoding and retrieval, but not consolidation of spatial information. In addition, muscimol but not CNQX induced impairments during a cued version of the WM task, and marked anxiety in the elevated plus maze. These results confirm the involvement of the LHb in higher cognitive functions. They further suggest a dichotomy between the role of glutamatergic and other inputs to the LHb in hippocampus-dependent memory processing, as well as in emotional aspects of goal-directed behaviors.

One ring to rule them all?--Temporospatial specificity of deep brain stimulation for treatment-resistant depression.

Deep brain stimulation (DBS) for intractable cases of depression has emerged as a valuable therapeutic option during the last decade. While several locations have been intensely investigated in recent years, the literature is lacking an all-encompassing perspective thereupon asking if and how these stimulation sites relate to each other and what this may imply for the underlying mechanisms of action of this treatment modality. We aim at proposing a model of DBS mechanism of action with particular focus on several puzzling aspects regarding an apparent temporo-spatial specificity of antidepressant action, i.e. the discrepancy between protracted response after initiation of stimulation and rapid relapse upon discontinuation, as well as differential effects on psychopathology. We suggest that the pre-treatment depressive state is determined by the interaction of individual traits with dysfunctional adaptive processes as responses to stress, resulting in a disease-associated, overtly dysfunctional, equilibrium. The antidepressant action of DBS is thought to modify and re-set this equilibrium in a temporospatially distinct manner by influencing the activity states of two different brain circuitries. The idea of sequential and temporospatially distinct mechanisms of action bears implications for the assessment of psychopathology and behavior in clinical and preclinical studies as well as investigations into brain circuit activity states.

Interactions between the lateral habenula and the hippocampus: implication for spatial memory processes.

The lateral habenula (LHb) is an epithalamic structure connected with both the basal ganglia and the limbic system and that exerts a major influence on midbrain monoaminergic nuclei. The current view is that LHb receives and processes cortical information in order to select proper strategies in a variety of behavior. Recent evidence indicates that LHb might also be implicated in hippocampus-dependent memory processes. However, if and how LHb functionally interacts with the dorsal hippocampus (dHPC) is still unknown. We therefore performed simultaneous recordings within LHb and dHPC in both anesthetized and freely moving rats. We first showed that a subset of LHb cells were phase-locked to hippocampal theta oscillations. Furthermore, LHb generated spontaneous theta oscillatory activity, which was highly coherent with hippocampal theta oscillations. Using reversible LHb inactivation, we found that LHb might regulate dHPC theta oscillations. In addition, we showed that LHb silencing altered performance in a hippocampus-dependent spatial recognition task. Finally, increased coherence between LHb and dHPC was positively correlated to the memory performance in this test. Collectively, these results suggest that LHb functionally interacts with the hippocampus and is involved in hippocampus-dependent spatial information processing.

Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze.

Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with sham-operated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21 h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal-dependent memory.

The match/mismatch of visuo-spatial cues between acquisition and retrieval contexts influences the expression of response vs. place memory in rats.

Animals can perform goal-directed tasks by using response cues or place cues. The underlying memory systems are occasionally presented as competing. Using the double-H maze test (Pol-Bodetto et al.), we trained rats for response learning and, 24 h later, tested their memory in a 60-s probe trial using a new start place. A modest shift of the start place (translation: 60-cm to the left) provided a high misleading potential, whereas a marked shift (180° rotation; shift to the opposite) provided a low misleading potential. We analyzed each rat's first arm choice (to assess response vs. place memory retrieval) and its subsequent search for the former platform location (to assess the persistence in place memory or the shift from response to place memory). After the translation, response memory-based behavior was found in more than 90% rats (24/26). After the rotation, place memory-based behavior was observed in 50% rats, the others showing response memory or failing. Rats starting to use response cues were nevertheless able to subsequently shift to place ones. A posteriori behavioral analyses showed more and longer stops in rats starting their probe trial on the basis of place (vs. response) cues. These observations qualify the idea of competing memory systems for responses and places and are compatible with that of a cooperation between both systems according to principles of match/mismatch computation (at the start of a probe trial) and of error-driven adjustment (during the ongoing probe trial).

The ventral hippocampus is necessary for expressing a spatial memory.

Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two post-acquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.

Electrical high frequency stimulation in the dorsal striatum: Effects on response learning and on GABA levels in rats.

Electrical high frequency stimulation (HFS) has been used to treat various neurological and psychiatric diseases. The striatal area contributes to response learning and procedural memory. Therefore, we investigated the effect of striatal HFS application on procedural/declarative-like memory in rats. All rats were trained in a flooded Double-H maze for three days (4 trials/day) to swim to an escape platform hidden at a constant location. The starting place was the same for all trials. After each training session, HFS of the left dorsal striatum was performed over 4h in alternating 20 min periods (during rest time, 10a.m. to 3p.m.). Nineteen hours after the last HFS and right after a probe trial assessing the rats' strategy (procedural vs. declarative-like memory-based choice), animals were sacrificed and the dorsal striatum was quickly removed. Neurotransmitter levels were measured by HPLC. Stimulated rats did not differ from sham-operated and control rats in acquisition performance, but exhibited altered behavior during the probe trial (procedural memory responses being less frequent than in controls). In stimulated rats, GABA levels were significantly increased in the dorsal striatum on both sides. We suggest that HFS of the dorsal striatum does not alter learning behavior in rats but influences the strategy by which the rats solve the task. Given that the HFS-induced increase of GABA levels was found 19 h after stimulation, it can be assumed that HFS has consequences lasting for several hours and which are functionally significant at a behavioral level, at least under our stimulation (frequency, timing, location, side and strength of stimulation) and testing conditions.

Spatial memory alterations by activation of septal 5HT 1A receptors: no implication of cholinergic septohippocampal neurons.

INTRODUCTION: In rats, activation of medial septum (MS) 5-HT(1A) receptors with the 5-HT(1A)/5-HT(7) receptor agonist 8-OH-DPAT disrupts encoding and consolidation, but not retrieval of a spatial memory in the water maze task. These findings might be explained by an action of 8-OH-DPAT on 5-HT(1A) receptors located on cholinergic neurons which the drug could transiently hyperpolarise. If so, selective damage of these neurons should mimic the effects of 8-OH-DPAT, or, at least, synergistically interfere with them. METHODS: To test this hypothesis, rats were subjected to intraseptal infusions of 8-OH-DPAT (or phosphate-buffered saline) during acquisition of a water maze task before and/or after 192 IgG-saporin-induced MS cholinergic lesion (vs. sham-operated). RESULTS: We confirmed that only pre-acquisition intraseptal 8-OH-DPAT infusions prevented learning and subsequent drug-free retrieval of the platform location in intact rats and found that (1) the cholinergic lesion did not prevent recall of the platform location, and (2) the impairing effects of 8-OH-DPAT were similar in sham-operated and lesioned rats, whether naïve or not, to the task before lesion surgery. CONCLUSIONS: An action of 8-OH-DPAT on only MS cholinergic neurons is not sufficient to account for the drug-induced memory impairments. A concomitant 8-OH-DPAT-induced hyperpolarisation of cholinergic and/or GABAergic and/or glutamatergic neurons (intact rats), or of only GABAergic and/or glutamatergic ones after cholinergic lesion, might be necessary to obliterate task acquisition, confirming that, in the MS, (1) the three neuronal populations could cooperate to process hippocampal-dependent information, and (2) non-cholinergic septohippocampal neurons might be more important than cholinergic ones in serotonin-induced modulation of hippocampus-dependent memory processing.

Septohippocampal pathways contribute to system consolidation of a spatial memory: sequential implication of GABAergic and cholinergic neurons.

Studies of the neuropharmacological substrates of spatial memory formation have focused on the contribution of septohippocampal pathways. Although these pathways include, among others, cholinergic and GABAergic fibers innervating the hippocampus, research has essentially been oriented towards the role of their cholinergic component. Recently, a few studies investigated the role of GABAergic septohippocampal projections. These only focused on almost immediate or recent memory and yielded discrepant results. GABAergic lesions impaired learning or had no effects. Given the role of the hippocampus in memory consolidation and the potential modulatory influence of the septum on hippocampal function, it is relevant to study the role of the septohippocampal interface in memory stabilization. We performed investigations with relatively selective lesions of GABAergic (using oxerin-saporin) or/and cholinergic (using 192 IgG-saporin) medial septum/vertical limb of the diagonal band of Broca (MS/vDBB) neurons in rats, and assessed acquisition of a spatial memory and its subsequent recall in the water maze. Following a 6-day training phase during which all groups improved performance to comparable levels, retention was tested 1, 5, or 25 days later. At the 1-day delay, all groups performed above chance and did not differ significantly among each other. At the 5-day delay, only rats with GABAergic or combined lesions exhibited a retention deficit. At the 25-day delay, all three lesion groups performed at chance level; in these groups, performance was significantly lower than that found in sham-operated rats. Immunochemical and histochemical verifications of the lesion extent/selectivity showed extensive GABAergic damage after intraseptal orexin-saporin infusions or cholinergic damage after 192 IgG-saporin infusions, with relatively limited damage to the other neurotransmitter system. Our data show that GABAergic and cholinergic septohippocampal neurons both contribute to memory stabilization, and could do so in a sequential way: GABAergic processes could be engaged at an earlier stage than cholinergic ones during system consolidation of a spatial memory.

The double-H maze test, a novel, simple, water-escape memory task: acquisition, recall of recent and remote memory, and effects of systemic muscarinic or NMDA receptor blockade during training.

To explore spatial cognition in rodents, research uses maze tasks, which differ in complexity, number of goals and pathways, behavioural flexibility, memory duration, but also in the experimenter's control over the strategy developed to reach a goal (e.g., allocentric vs. egocentric). This study aimed at validating a novel spatial memory test: the double-H maze test. The transparent device made of an alley with two opposite arms at each extremity and two in its centre is flooded. An escape platform is submerged in one arm. For experiments 1-3, rats were released in unpredictable sequences from one of both central arms to favour an allocentric approach of the task. Experiment 1 (3 trials/day over 6 days) demonstrated classical learning curves and evidence for recent and nondegraded remote memory performance. Experiment 2 (2 days, 3 trials/day) showed a dose-dependent alteration of task acquisition/consolidation by muscarinic or NMDA receptor blockade; these drug effects vanished with sustained training (experiment 3; 4 days, 3 trials/day). Experiment 4 oriented rats towards a procedural (egocentric) approach of the task. Memory was tested in a misleading probe trial. Most rats immediately switched from response learning-based to place learning-based behaviour, but only when their initial view on environmental cues markedly differed between training and probe trials. Because this simple task enables the formation of a relatively stable memory trace, it could be particularly adapted to study consolidation processes at a system level or/and the interplay between procedural and declarative-like memory systems.