Visual landmark information gains control of the head direction signal at the lateral mammillary nuclei.

The neural representation of directional heading is conveyed by head direction (HD) cells located in an ascending circuit that includes projections from the lateral mammillary nuclei (LMN) to the anterodorsal thalamus (ADN) to the postsubiculum (PoS). The PoS provides return projections to LMN and ADN and is responsible for the landmark control of HD cells in ADN. However, the functional role of the PoS projection to LMN has not been tested. The present study recorded HD cells from LMN after bilateral PoS lesions to determine whether the PoS provides landmark control to LMN HD cells. After the lesion and implantation of electrodes, HD cell activity was recorded while rats navigated within a cylindrical arena containing a single visual landmark or while they navigated between familiar and novel arenas of a dual-chamber apparatus. PoS lesions disrupted the landmark control of HD cells and also disrupted the stability of the preferred firing direction of the cells in darkness. Furthermore, PoS lesions impaired the stable HD cell representation maintained by path integration mechanisms when the rat walked between familiar and novel arenas. These results suggest that visual information first gains control of the HD cell signal in the LMN, presumably via the direct PoS → LMN projection. This visual landmark information then controls HD cells throughout the HD cell circuit.

Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors.

Paeoniflorin (PF, C23H28O11), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM). Immunohistochemical study revealed that PF decreased c-fos expression in the histaminergic tuberomammillary nucleus (TMN). The sleep-promoting effects and changes in c-fos induced by PF were reversed by 8-cyclopentyl-1,3-dimethylxanthine (CPT), an adenosine A1 receptor antagonist, and PF-induced sleep was not observed in adenosine A1 receptor knockout mice. Whole-cell patch clamping in mouse brain slices showed that PF significantly decreased the firing frequency of histaminergic neurons in TMN, which could be completely blocked by CPT. These results indicate that PF increased NREM sleep by inhibiting the histaminergic system via A1 receptors.

A postmortem assessment of mammillary body volume, neuronal number and densities, and fornix volume in subjects with mood disorders.

Mammillary bodies are relay nuclei within limbic and extralimbic connections. Whereas other subcortical brain structures have been found to be altered in depression, no current information exists regarding the pathomorphology of mammillary bodies in affective disorders. We studied the postmortem brains of 19 human subjects with mood disorders (9 with major depressive disorder and 10 with bipolar I disorder) and 20 control individuals and assessed the mammillary body and fornix volumes, number of neurons and neuronal densities. We found that male control subjects have significantly larger mammillary bodies compared with females. In addition, control subjects of both sexes with the diagnosis/cause of death of "heart failure/insufficiency" had significantly smaller mammillary body volumes compared with non-psychiatric patients who died from other causes. When estimating the mammillary bodies volumes of patients with depression compared with control subjects, a significant reduction of the left mammillary body volume was found in patients with bipolar disorder, but not in patients with major depression. However, significant depression-associated mammillary body volume reductions were found between the control subjects who did not die of heart failure and patients with major depression and bipolar disorder. Moreover, the MB volumes of control subjects who died of heart failure were in the range exhibited by subjects with depression. There was no significant influence of suicidal behavior on mammillary volumes observed. Moreover, no significant group differences in the total neuronal number or neuronal density were found between the controls, subjects with major depression and subjects with bipolar disorder. Furthermore, the fornix volumes were significantly reduced only in the control subjects with heart failure. Taken together, these results show that the mammillary bodies are compromised in depression.

Acute ethanol induces behavioral changes and alters c-fos expression in specific brain regions, including the mammillary body, in zebrafish.

Ethanol is one of the most commonly abused substances in the world, and ethanol abuse and dependence disorders represent major societal problems. However, appropriate treatment is lacking as we still do not fully understand the molecular bases of these disorders. The zebrafish is one of the model organisms utilized for studying such mechanisms. In this study, we examined the effects of acute ethanol administration on the behavior of zebrafish, and we also analyzed correlated gene expression changes using whole-mount in situ hybridization focusing on a number of genes associated with different neurotransmitter systems, stress response, and neuronal activity. We found ethanol treatment to result in hyperactivity and reduced shoal cohesion compared to control. Analysis of c-fos expression demonstrated altered activity patterns in certain brain regions, including intense activation of the mammillary body in zebrafish with acute ethanol treatment. We also found reduced level of gad1b expression in the cerebellum of ethanol treated fish compared to control. However, we could not detect significant changes in the expression level of other genes, including vglut2b, th, crh, hdc, avp, pomc, and galn in ethanol treated fish compared controls. Our results suggest that zebrafish is a promising animal model for the study of mechanisms underlying alcohol induced behavioral changes and alcohol related human disorders.

Nicotinic receptor mechanism in supramammillary nucleus mediates physiological regulation of neural activity in dorsal hippocampal field CA1 of anaesthetized rat.

Evidence suggests that stimulation of the region of the rostral pontine oralis (RPO) nucleus and the peripheral application of a noxious stimulus activates an ascending system that also modulates hippocampal neural responses during behavioral arousal. Indeed, the two stimuli and behavioral arousal elicit theta activation and the suppression of population spikes (PS) in dorsal hippocampus field CA1. Interestingly, such neural responses in CA1 are also elicited by microinjection of the cholinergic agonist carbachol into the hypothalamic supramammillary nucleus (SuM). In the present in vivo electrophysiological study, we tested the hypothesis that cholinergic neural elements in the SuM modulate the neural drive to CA1 on RPO stimulation or the peripheral application of a noxious stimulus. Pharmacological investigation showed that intra-SuM microinjection of either a muscarinic or a nicotinic receptor antagonist attenuated the SuM carbachol-induced neural effects in CA1, namely, theta activation and PS suppression. However, neither antagonist attenuated the CA1 effects of intra-SuM microinjection of the excitatory neurotransmitter glutamate. Subsequent investigations revealed that microinjection of only the nicotinic antagonist, mecamylamine, into the lateral SuM selectively attenuated the responses elicited in CA1 by stimulation of the RPO or on nociceptive stimulation with hind paw injection of formalin (5%, 0.05 ml); whereas, microinjection of mecamylamine into the medial SuM did not affect the hippocampal responses elicited by either type of stimulation. Furthermore, application of mecamylamine into the lateral SuM attenuated the CA1 responses induced by injection of formalin into the contralateral, but not the ipsilateral hind paw. The lateralization of drug effect is consistent with the predominant unilateral anatomical connections between the SuM and the septohippocampal region. These findings provide novel evidence that nicotinic cholinoceptive neurons in the lateral SuM are common elements of the neural drive(s) to the hippocampus on RPO activation and noxious stimulation.

Environmental hydrocarbons produce degeneration in cat hypothalamus and optic tract.

2,5-Hexanedione, the principal neurotoxic metabolite of the industrial solvents n-hexane and methyl n-butyl ketone causes axonal degeneration in the mammillary body and visual nuclei of cats. Prolonged, low-level exposure to hydrocarbons in the environment may cause premature deterioration in areas of the human brain vital for perception and behavior.

Temporary inactivation of the supramammillary area impairs spatial working memory and spatial reference memory retrieval.

The aim of our study was to examine the supramammillary (SuM) area involvement in spatial memory. Sprague-Dawley rats with chronically implanted cannula in the supramammillary area were trained in two spatial memory tasks with different memory demands: reference and working memory. In the spatial reference memory task, the rats received microinjections in the SuM area of tetrodotoxin (TTX) (0.5 ng diluted in 0.5 microL of saline) or saline (0.5 microL). The microinjections were administered 30 min before the spatial training (day 4) (to assess the effect on acquisition) and on the following two days (days 5 and 6) the training was conducted without microinjections (to study the effect on consolidation). On the last training day (day 7), in order to assess the retrieval of spatial information, the rats received the microinjections 30 min before the spatial training. The spatial working memory used was a delayed-matching-to-position (DMTP) task. Spatial training was performed for seven days. During the first three days of the spatial training, the rats achieved a good spatial knowledge and learnt the working memory rule necessary to solve the spatial task. On days 4 and 6, the rats received microinjections to study involvement of the SuM area in working memory. The results showed that temporary inactivation of SuM area impairs both the rat's ability to solve a spatial working memory task with DMTP demands and the recovery of spatial information in a spatial reference memory task. We suggest that SuM area is involved in the rearrangement of spatial information during spatial working memory tasks with DMTP memory demands.

Lesions within the head direction system reduce retrosplenial c-fos expression but do not impair performance on a radial-arm maze task.

The lateral mammillary nuclei are a central structure within the head direction system yet there is still relatively little known about how these nuclei contribute to spatial performance. In the present study, rats with selective neurotoxic lesions of the lateral mammillary nuclei were tested on a working memory task in a radial-arm maze. This task requires animals to distinguish between eight radially-oriented arms and remember which arms they have entered within a session. Even though it might have been predicted that this task would heavily tax the head direction system, the lesion rats performed equivalently to their surgical controls on this task; no deficit emerged even when the task was made more difficult by rotating the maze mid-way through testing in order to reduce reliance on intramaze cues. Rats were subsequently tested in the dark to increase the use of internally generated direction cues but the lesion rats remained unimpaired. In contrast, the lateral mammillary nuclei lesions were found to decrease retrosplenial c-Fos levels. These results would suggest that the head direction system is not required for the acquisition of the standard radial-arm maze task. It would also suggest that small decreases in retrosplenial c-Fos are not sufficient to produce behavioural impairments.

The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats.

RATIONALE: Ketamine or MK-801 induced sensorimotor gating deficit, but the underlying neural mechanisms are not completely known. We have previously demonstrated that the medial septum (MS) mediated the phencyclidine-induced deficit in prepulse inhibition of the acoustic startle (PPI) in rats. OBJECTIVES: We investigated the involvement of the supramammillary area (SUM) to MS pathway in PPI impairment and behavioral hyperlocomotion induced by MK-801 or ketamine in rats and correlated the behavioral deficits with hippocampal gamma wave increase. MATERIALS AND METHODS: Ketamine (6 mg/kg, s.c.) or MK-801 (0.5 mg/kg, i.p.) was administered after infusion of saline or the GABA(A) receptor agonist, muscimol (0.25 microg), into the MS or SUM. Locomotion, PPI, and hippocampal electroencephalogram (EEG) were recorded. RESULTS: MK-801 or ketamine induced PPI impairment and behavioral hyperlocomotion, accompanied by an increase in hippocampal gamma waves (30-100 Hz). The changes in behavior and gamma waves induced by ketamine or MK-801 were antagonized by pre-infusion of muscimol, but not saline, into the SUM or MS. Infusion of muscimol into the SUM alone did not significantly affect PPI, but it suppressed spontaneous locomotor behavior and hippocampal EEG. Infusion of ionotropic glutamate receptor antagonists into the MS did not affect the PPI deficit or the gamma wave increase after MK-801. CONCLUSIONS: A non-glutamatergic component of the supramammillo-septal pathway mediates the hyperlocomotion and the deficits in PPI induced by MK-801 or ketamine. Inactivation of the MS or SUM normalized both the hippocampal gamma waves and the behavioral deficits (PPI impairment and hyperlocomotion).

Serotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat.

Theta activity has been related to the processing of spatial information and the formation of hippocampus-dependent memory. The medial septum (MS) plays an important role in the control and coordination of theta activity, as well as in the modulation of learning. It has been established that increased serotonergic activity may desynchronize theta activity, while reduced serotonergic activity produces continuous and persistent theta activity in the hippocampus. We investigate whether serotonin acting on the medial septum could modify spatial learning and the functional relationship between septo-hippocampal and septo-mammillary theta activity. The serotonin was depleted (5HT-D) from the medial septum by the injection of 5,7 DHT (5,7- dihydroxytryptamine). Theta activity was recorded in the dorsal hippocampus, MS and mammillary nuclei (SUM, MM) of Sprague-Dawley male rats during spatial learning in the Morris water maze. Spatial learning was facilitated, and the frequency of the hippocampal theta activity during the first days of training increased (to 8.5Hz) in the 5HT-D group, unlike the vehicle group. Additionally, the coherence between the MS-hippocampus and the MS-mammillary nuclei was higher during the second day of the test compared to the vehicle group. We demonstrated that septal serotonin depletion facilitates the acquisition of spatial information in association with a higher functional coupling of the medial septum with the hippocampus and mammillary nuclei. Serotonin, acting in the medial septum, modulates hippocampal theta activity and spatial learning.

The effect of pharmacological inactivation of the mammillary body and anterior thalamic nuclei on hippocampal theta rhythm in urethane-anesthetized rats.

The mammillary body (MB) and the anterior thalamic nuclei (ATN) are closely related structures, which take part in learning and memory processes. However, the exact role of these structures has remained unclear. In both structures neurons firing according to hippocampal theta rhythm have been found, mainly in the medial mammillary nucleus (MM) and anteroventral thalamic nucleus (AV). These neurons are driven by descending projections from the hippocampal formation and are thought to convey theta rhythm back to the hippocampus (HP). We argue that the MB-ATN axis not only relays theta signal, but may also modulate it. To examine it, we performed a pharmacological inactivation of the MM and AV by local infusion of procaine, and measured changes in theta activity in selected structures of the extended hippocampal system in urethane-anesthetized rats. The inactivation of the MM resulted in decrease in EEG power in the HP and AV, the most evidently in the lower theta frequency bands, i.e. 3-5Hz in the HP (down to 9.2% in 3- to 4-Hz band and 37.6% in 4- to 5-Hz band, in comparison to the power in the control conditions) and 3-4Hz in the AV (down to 24.9%). After the AV inactivation, hippocampal EEG power decreased in theta frequency bands of 3-8Hz (down to 61.6% in 6- to 7-Hz band and 69.4% in 7- to 8-Hz band). Our results suggest that the role of the MB-ATN axis in regulating theta rhythm signaling may be much more important than has been speculated so far.

Expression of c-Fos protein in medial septum/diagonal band of Broca and CA3 region, associated with the temporary inactivation of the supramammillary area.

The supramammillary (SuM) area is part of the diencephalic nuclei comprising the mammillary bodies, and is a key structure in the memory and spatial learning processes. It is a critical region in the modulation/generation of hippocampal theta rhythm. In addition, many papers have recently shown a clear involvement of this structure in the processes of spatial learning and memory in animal models, although it is still not known how it modulates spatial navigation and response emotional. The aim of the present research was to study the effect of the temporary inactivation of the SuM area on synaptic plasticity of crucial structures in the formation of spatial memory and emotional response. Sprague-Dawley rats were asigned in three groups: a control group where the animals were not subjected to any treatment, and two groups where the rats received microinjections of tetrodotoxin (TTX) in the SuM area (5ng diluted in 0.5µl of saline) or saline (0.5µl). The microinjections were administered 90min before the perfusion. Later, cellular activity in medial septum/diagonal band of Broca (MS/DBB) and CA3 region of the dorsal hippocampus was assessed, by measuring the immediate early gene c-fos. The results show a clear hiperactivity cellular in medial septum/diagonal band of Broca and a clear hypoactivity cellular in the CA3 region of the hippocampus when there was a functional inactivation of the SuM area. It suggests that the SuM area seems to be part of the connection and information input pathways to CA3 region of the hippocampal formation, key for proper functioning in spatial memory and emotional response.

Rewarding effects of AMPA administration into the supramammillary or posterior hypothalamic nuclei but not the ventral tegmental area.

We examined whether injections of the excitatory amino acid AMPA are rewarding when injected into the posterior hypothalamus and ventral tegmental area. Rats quickly learned to lever-press for infusions of AMPA into the supramammillary or posterior hypothalamic nuclei but failed to learn to lever-press for similar injections into the ventral tegmental areas. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, induced conditioned place preference. The rewarding effects of AMPA appear to be mediated by AMPA receptors, because coadministration of the AMPA antagonist CNQX blocked the rewarding effects of AMPA, and administration of the enantiomer R-AMPA did not mimic the rewarding effects. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, also increased extracellular dopamine concentrations in the nucleus accumbens. Pretreatment with the D1 dopamine antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] led to extinction of AMPA self-administration. These findings implicate posterior hypothalamic regions in reward function and suggest that reward mechanisms localized around the ventral tegmental area are more complex than has been assumed recently.

The head direction cell system and behavior: The effects of lesions to the lateral mammillary bodies on spatial memory in a novel landmark task and in the water maze.

The head direction system is composed of neurons found in a number of connected brain areas that fire in a sharply tuned, directional way. The function of this system, however, has not been fully established. To assess this, we devised a novel spatial landmark task, comparable to the paradigms in which stimulus control has been assessed for spatially tuned neurons. The task took place in a large cylinder and required rats to dig in a specific sand cup, from among 16 alternatives, to obtain a food reward. The reinforced cup was in a fixed location relative to a salient landmark, and probe sessions confirmed that the landmark exerted stimulus control over the rats' cup choices. To assess the contribution of the head direction cell system to this memory task, half of the animals received ibotenic acid infusions into the lateral mammillary nuclei (LMN), an essential node in the head direction network, while the other received sham lesions. No differences were observed in performance of this task between the 2 groups. Animals with LMN lesions were impaired, however, in reversal learning on a water maze task. These results suggest that the LMN, and potentially the head direction cell system, are not essential for the use of visual landmarks to guide spatial behavior.

Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.

Patients suffering from major depression often experience memory deficits even after the remission of mood symptoms, and many antidepressant drugs do not affect, or impair, memory in animals and humans. However, some antidepressant drugs, after a single dose, enhance cognition in humans (Harmer et al., 2009). To compare different classes of antidepressant drugs for their potential as memory enhancers, we used a version of the novel object recognition task in which rats spontaneously forget objects 24 hr after their presentation. Antidepressant drugs were injected systemically 30 min before or directly after the training phase (Session 1 [S1]). Post-S1 injections were used to test for specific memory-consolidation effects. The noradrenaline reuptake inhibitors reboxetine and atomoxetine, as well as the serotonin noradrenaline reuptake inhibitor duloxetine, injected prior to S1 significantly enhanced recognition memory. In contrast, the serotonin reuptake inhibitors citalopram and paroxetine and the cyclic antidepressant drugs desipramine and mianserin did not enhance recognition memory. Post-S1 injection of either reboxetine or citalopram significantly enhanced recognition memory, indicating an effect on memory consolidation. The fact that citalopram had an effect only when injected after S1 suggests that it may counteract its own consolidation-enhancing effect by interfering with memory acquisition. However, pretreatment with citalopram did not attenuate reboxetine's memory-enhancing effect. The D1/5-receptor antagonist SCH23390 blunted reboxetine's memory-enhancing effect, indicating a role of dopaminergic transmission in reboxetine-induced recognition memory enhancement. Our results suggest that antidepressant drugs specifically inhibiting noradrenaline reuptake enhance cognition and may be beneficial in the treatment of cognitive symptoms of depression.

Group II selective metabotropic glutamate receptor agonists and local cerebral glucose use in the rat.

The novel mGluR agonist LY354740 and a related analogue LY379268 are selective for mGluR2/3 receptors and are centrally active after systemic administration. In this study, rates of local cerebral glucose use were measured using the [14C]2-deoxyglucose autoradiographic technique to examine the functional consequences of their systemic administration in the conscious rat. Both LY354740 (0.3, 3.0, 30 mg/kg) and LY379268 (0.1, 1.0, 10 mg/kg) produced dose-dependent changes in glucose use. After LY354740 (3.0mg/kg), 4 of the 42 regions measured showed statistically significant changes from vehicle-treated controls: red nuclei (-16%), mammillary body (-25%), anterior thalamus (-29%), and the superficial layer of the superior colliculus (+50%). An additional 15 regions displayed significant reductions in function-related glucose use (P < .05) in animals treated with LY354740 (30 mg/ kg). LY379268 (0.1, 1.0, 10 mg/kg) produced changes in glucose metabolism in 20% of the brain regions analyzed. Significant increases (P < .05) in glucose use were evident in the following: the superficial layer of the superior colliculus (+81%), locus coeruleus (+57%), genu of the corpus callosum (+31%), cochlear nucleus (+26%), inferior colliculus (+20%), and the molecular layer of the hippocampus (+14%). Three regions displayed significant decreases: mammillary body (-34%), anteroventral thalamic nucleus (-28%), and the lateral habenular nucleus (-24%). These results show the important functional involvement of the limbic system together with the participation of components of different sensory systems in response to the activation of mGluR2 and mGluR3 with LY354740 and LY379268.

Opposite modulation of histaminergic neurons by nociceptin and morphine.

We have studied the effects of nociceptin/orphanin FQ on the histaminergic neurons in the tuberomammillary (TM) nucleus and compared them with the actions of opioid agonists. Intracellular recordings of the membrane potential were made with sharp electrodes from superfused rat hypothalamic slices. Nociceptin strongly inhibited the firing of the TM neurons. In the concentration range 10-300 nM, nociceptin hyperpolarized the neurons in a dose-dependent and reversible manner. Insensitivity to tetrodotoxin indicated a postsynaptic effect which was associated with decreased input resistance. Voltage-current plots suggested the involvement of a potassium conductance which was highly sensitive to Ba(2+) and decreased by Cs(+), in keeping with the activation of an inwardly rectifying potassium channel. Morphine (20-100 microM) depolarized the TM neurons and increased their firing, and this effect was blocked by tetrodotoxin. Dynorphin A(1-13) at 100-300 nM did not affect the TM neurons. Nociceptin and morphine modulate the activity of the TM neurons, and most likely histamine release, in opposite ways. Histamine has an antinociceptive effect in the brain and may be involved in opioid-induced analgesia. Nociceptin might therefore influence pain transmission by inhibiting opioid-induced histamine release from the TM nucleus and also modulate other physiological mechanisms which have been ascribed to the histaminergic system.

Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain.

This study was designed to examine the interactions between the cannabinoid and enkephalinergic systems in the rat brain. To this aim, we have examined the effects of subchronic (5 days) administration (10 mg.kg-1.day-1; i.p.) of delta 9 -tetrahydrocannabinol (THC) or R-methanandamide (AM356) and chronic (18 days) administration with the synthetic cannabinoid receptor agonist CP-55,940 (1 mg.kg-1.day-1; i.p) on proenkephalin (PENK) mRNA levels in several brain regions of the rat. Twenty micrometer brain sections from striatum, nucleus accumbens, paraventricular nucleus, ventromedial nucleus, periaqueductal grey matter and mammillary nucleus were hybridized with an oligonucleotide probe complementary to PENK using in situ hybridization technique. Subchronic administration of THC or AM356 increased PENK mRNA levels in the ventromedial nucleus of the hypothalamus, (82%) and (39%), in the periaqueductal grey matter, (97%) and (49%), and mammillary nucleus, (43%) and (9%), respectively. In contrast, both drugs were without effect in the striatum and nucleus accumbens. On the other hand, chronic administration of CP-55,940 increased PENK mRNA levels in the striatum (44%), nucleus accumbens (25%), paraventricular (31%) and ventromedial nuclei of the hypothalamus (41%). These results revealed that chronic cannabinoid administration increases opioid gene expression in the rat central nervous system and suggest an interaction between the cannabinoid and enkephalinergic systems that may be part of a molecular integrative response to behavioral and neurochemical alterations that occur in cannabinoid drug abuse.

MRI morphometry of mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leukemia: multivariate models of early and late developing memory subsystems.

Neurotoxic intrathecal chemotherapy for childhood acute lymphoblastic leukemia (ALL) affects developing structures and functions of memory and learning subsystems selectively. Results show significant reductions in magnetic resonance imaging morphometry of mamillary bodies, components of the corticolimbic-diencephalic subsystem subserving functionally later developing, single-trial memory, nonsignificant changes in bilateral heads of the caudate nuclei, components of the corticostriatal subsystem subserving functionally earlier developing, multitrial learning, significant reductions in prefrontal cortical volume, visual and verbal single-trial memory deficits, and visuospatial, but not verbal, multitrial learning deficits. Multiple regression models provide evidence for partial dissociation and connectivity between the subsystems, and suggest that greater involvement of caudate may compensate for inefficient corticolimbic-diencephalic components.

Effects of ibotenic acid lesions of the dorsal hippocampus on contextual fear conditioning in mice: comparison with mammillary body lesions.

The goals of the present study were to determine if ibotenic acid lesions of the dorsal hippocampus (dHPC) or of mammillary body (MB) of the hypothalamus would induce similar contextual conditioning deficit in a fear-conditioning paradigm, previously developed in mice [Eur. J. Neurosci. 12 (2000) 2575]. Results showed that ibotenic acid lesions of the dHPC or of the MB both induced severe deficits on contextual conditioning but spared auditory conditioning, as compared to controls. This study provides direct evidence for an involvement of dHPC neurones in contextual fear conditioning and is first to demonstrate an involvement of the MB in the mediation of contextual fear conditioning.