Wei-Ning Zhang

Regional dissociations within the hippocampus—memory and anxiety

The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latters role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughtons theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.

Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory

Lesions restricted to the dorsal, but not the ventral, hippocampus severely impair the formation of spatial memory. This dissociation was first demonstrated using the water maze task. The present study investigated whether the dorsal and the ventral hippocampus are involved differentially in spatial reference and spatial working memory using a four‐baited/four‐unbaited version of the eight‐arm radial maze task. This test allows the concurrent evaluation of reference and working memory with respect to the same set of spatial cues, and thereby enables a within‐subjects within‐task comparison between the two forms of memory functions. Rats with N‐methyl‐d‐aspartic acid‐induced excitotoxic lesions of the dorsal hippocampus, ventral hippocampus or both were compared with sham and unoperated controls. We showed that dorsal lesions were as effective as complete lesions in severely disrupting both reference and working spatial memory, whereas rats with ventral lesions performed at a level comparable with controls. These results lend further support to the existence of a functional dissociation between the dorsal and the ventral hippocampus, with the former being preferentially involved in spatial learning.

The ventral hippocampus and fear conditioning in rats: different anterograde amnesias of fear after infusion of N-methyl-D-aspartate or its noncompetitive antagonist MK-801 into the ventral hippocampus.

Previous studies on hippocampal involvement in classical fear conditioning mainly focused on the dorsal hippocampus and conditioning to a context. However, in line with the strong interconnectivity of the ventral hippocampus with amygdala and nucleus accumbens, more recent studies indicated an even more global role for the ventral hippocampus in fear conditioning. The present study examined the formation of classical fear conditioning to explicit and contextual cues following stimulation or blockade of N-methyl-D-aspartate (NMDA) receptors in the ventral hippocampus. NMDA (0.5 microg/side) or the noncompetitive NMDA antagonist MK-801 (dizocilpine; 6.25 microg/side) were bilaterally infused into the ventral hippocampus of Wistar rats before fear conditioning to explicit and contextual cues. Conditioned fear was assessed using an automated measurement of freezing. NMDA stimulation of the ventral hippocampus blocked fear conditioning to both the tone and the context. MK-801 selectively blocked fear conditioning to the context. Our results support that the ventral hippocampus plays a role in the formation of classical fear conditioning. The specific anterograde amnesia for fear to a context after MK-801 infusion into the ventral hippocampus indicates that formation of classical fear conditioning to a context but not to a tone requires activation of NMDA receptor-mediated processes in the ventral hippocampus. Given that NMDA stimulation of the ventral hippocampus disrupts also processes not mediated by NMDA receptors, the complete anterograde amnesia following NMDA infusion into the ventral hippocampus might be due to the concurrent severe disruption of normal ventral hippocampal activity. However, strong stimulation of the ventral hippocampus might also disrupt fear conditioning by interfering with processes in the projection areas of the ventral hippocampus, such as the amygdala or the nucleus accumbens. In addition, we report that MK-801 (6.25 microg/side) infusion into the ventral hippocampus increased locomotor activity in the open field.

Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats

Disruption of prepulse inhibition (PPI) induced by NMDA receptor antagonists, such as MK801, has been used as an animal model of positive and negative symptoms of schizophrenia. Previous studies suggested that atypical, but not typical, neuroleptics can selectively restore MK801-induced PPI disruption and that such selectivity may depend on strain differences. The present study re-examined PPI disruption by systemic MK801 in Wistar (WS) and Sprague-Dawley (SD) strains, and addressed the issue whether clozapine (atypical), compared to haloperidol (typical), effectively antagonizes MK801-induced PPI disruption. In addition, we tested the effects of bilateral microinfusion of MK801 into the ventral hippocampus in WS. Systemic MK801 disrupted PPI in both strains. Neither clozapine nor haloperidol antagonized MK801-induced PPI in either strain. Our clozapine data do not agree with previous reports of clozapines ability to antagonize MK801-induced PPI disruption. Similar to previous results with SD, MK801 infusion into the ventral hippocampus failed to affect PPI in WS. In our view, the selective ability of atypical neuroleptics to restore PPI disruption by NMDA antagonists, and to serve as a tool for identifying possible atypical neuroleptics, requires further examination. PPI disruption with systemic MK801 may be due to the blockade of NMDA receptors in multiple brain sites.

Differential expression of PSD proteins in age-related spatial learning impairments

Deficits in hippocampus-dependent spatial learning that are typical for a subpopulation of aged rats are not associated with loss of neurons or excitatory synapses but accompanied by significant reduction of postsynaptic density (PSD) area in perforated synapses. Here, we examined whether structural alterations in aged learning-impaired rats correlate with altered content of PSD proteins which are critically involved in normal synaptic function. Spatial memory tasks were used to separate male rats into young, aged learning-unimpaired and impaired groups. Semi-quantitative immunohistochemistry revealed significant alterations in the content of the AMPA receptor GluR1 subunit, PSD-95 and synGAP in the hippocampal formation of aged-learning impaired compared to aged-unimpaired and young rats. While synGAP expression was reduced, GluR1 and PSD95 levels were selectively increased in aged-learning-impaired subjects. These findings suggest that age-induced changes of the PSD protein expression levels are more pronounced in learning-impaired rats compared to unimpaired subjects and that the alterations in synaptic protein content may result in reduced synaptic function, potentially underlying the individual differences in mnemonic functions during aging.

Early deprivation leads to altered behavioural, autonomic and endocrine responses to environmental challenge in adult Fischer rats.

Depression is diagnosed on the basis of abnormal positive affects (anhedonia) and negative affects (low mood, helplessness, coping deficit, fatigue), and associated physiological abnormalities include hyperactivity of the HPA endocrine system and autonomic nervous system. Adverse early life environments, including parent–offspring emotional and physical neglect, are associated with traits of altered physiological and neurobiological function and long‐term predisposition to depression. Animal studies based on early life adversity can potentially yield environmental models of the developmental behavioural neurobiology of depression. In Wistar rats, we demonstrated that isolation of pups from dam and littermates at room temperature for 4 h per day on P1–14 (early deprivation, ED) led to adulthood anhedonia‐like traits of reduced motivation to obtain gustatory reward and reduced social motivation, relative to subjects left undisturbed during infancy (non‐handling, NH). We hypothesized that the depression‐like effects of ED would be even more pronounced and multiple in the stress hyper‐responsive Fischer rat strain. The effects of ED were studied relative to NH and 15 min of daily isolation (early handling, EH). Relative to NH and EH, which exhibited remarkably similar phenotypes, ED led, principally in males, to chronic traits of: reduced motivation for and consumption of gustatory reward; increased activity in the pre‐test and test phases of the forced swim test; reduced coping behaviour in an aversive environment; attenuated plasma corticosterone stress response to a normal plasma ACTH stress response; increased hypertensive response to a novel environment; and increased prefrontal cortical serotonin. High sensitivity to an aversive early environment in male Fischer rats therefore constitutes an important model for the study of affective development and its neurobiology.

Dissociation of function within the hippocampus: Effects of dorsal, ventral and complete excitotoxic hippocampal lesions on spatial navigation

The present study was designed to assess the possibility that sub-total ventral hippocampal lesions might leave intact a mechanism for only highly accurate navigation, whereas sub-total dorsal hippocampal lesions might leave intact a mechanism only for less precise navigation. Animals with selective dorsal, ventral or complete hippocampal lesions were tested in a water maze, in which the target platform was moved from trial to trial, but always within a defined area, instead of being at a fixed location. Hence, an animal that searched at exactly the point where the platform had been found on a previous trial would be disadvantaged, in comparison with an animal that searched in the right general area. This might favor animals capable of less precise navigation over those with very precise navigational abilities. In subsequent phases of the experiment, we additionally assessed, for comparison, performance with a fixed platform location, reversal learning in the water-maze, and performance on an elevated T-maze. Our results revealed no sign of any qualitative difference between the effects of the selective sub-total lesions when the water maze hidden platform location was varied within the defined area, and the effects in subsequent more conventionally used tests. Ventral hippocampal damage never led to a performance deficit. Dorsal hippocampal damage led to significantly poorer performance in only some test phases, and never led to any sign of improved performance.

Hyperactivity and disruption of prepulse inhibition induced by N-methyl-d-aspartate stimulation of the ventral hippocampus and the effects of pretreatment with haloperidol and clozapine

This study re-examined the hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the rat ventral hippocampus and compared how both effects were affected by pretreatment with either haloperidol or clozapine. While the hyperactivity is thought to depend on dopamine receptor activation in the nucleus accumbens, the dopamine D2-class receptor blocker haloperidol failed to antagonize the disruption of prepulse inhibition in previous studies. However, an ameliorative effect of the atypical neuroleptic clozapine on disruption of prepulse inhibition was suggested by our previous experiments [Zhang et al. (1999) NeuroReport 10, 1-6]. In the present study, bilateral infusion of N-methyl-D-aspartate (0.5microg/side) into the ventral hippocampus of Wistar rats increased open field locomotor activity and disrupted prepulse inhibition. Both effects were observed immediately after infusion but disappeared 24h later. Injection of haloperidol (0.2mg/kg) or clozapine (5mg/kg), 45min prior to N-methyl-D-aspartate infusion, totally antagonized the hyperactivity but did not affect the disruption of prepulse inhibition. We conclude that dopaminergic mechanisms are differentially involved in the hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus. Activation of accumbal dopamine receptors, which is blocked by clozapine and haloperidol to a comparable extent, seems to be crucial for the hyperactivity but not the disruption of prepulse inhibition. The present finding that both clozapine and haloperidol failed to antagonize the disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus is discussed with respect to our previous contrary finding concerning the ameliorative effect of clozapine and with respect to the disruption of prepulse inhibition in rats being considered as a model of sensorimotor gating deficits in schizophrenia.

Effects of hippocampal N-methyl-D-aspartate infusion on locomotor activity and prepulse inhibition: Differences between the dorsal and ventral hippocampus

Prepulse inhibition (PPI) of the acoustic startle response and open-field locomotor activity were measured after bilateral infusion of N-methyl-D-aspartate into the ventral (0.10, 0.25, 0.50 microg/side) and dorsal (0.10, 0.25, 0.50, 0.70 microg/side) hippocampus of Wistar rats. Dose-dependent hyperactivity and disruption of PPI--behavioral effects related to psychotic symptoms--were observed after ventral infusions but were virtually absent after dorsal infusions. This functional dorsal-ventral difference might be related to the different connections of the dorsal and ventral hippocampus with the amygdala, nucleus accumbens, and prefrontal cortex, which have been implicated in the regulation of locomotor activity and PPI. Hippocampal overactivity has been associated with schizophrenia. The findings suggest that overstimulation of the ventral hippocampal projections may contribute to behavioral outcomes related to psychotic symptoms.

Prepulse inhibition in rats with temporary inhibition/inactivation of ventral or dorsal hippocampus

Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating and is decreased in neuropsychiatric diseases, including schizophrenia. Hippocampal involvement in PPI has been the subject of several studies, in particular, as aberrant hippocampal activity has been associated with schizophrenia. In rats, chemical stimulation of the ventral hippocampus reduced PPI, while normal PPI was found following hippocampal lesions, suggesting that ventral hippocampal overactivity is detrimental for PPI, but that normal hippocampal activity does not contribute substantially to PPI. In the present study, we investigated the importance of hippocampal activity for PPI by examining PPI in Wistar rats with temporarily decreased hippocampal activity, aiming to avoid compensatory processes that may occur with permanent lesions. Bilateral ventral or dorsal hippocampal infusions of the gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol (1 microg/side) or the sodium-channel blocker tetrodotoxin (TTX, 10 ng/side) reduced PPI. This reduction is probably neuroleptic-resistant since haloperidol and clozapine did not antagonize the muscimol-induced decreases in PPI. PPI reduction by muscimol inhibition or TTX inactivation of the dorsal or ventral hippocampus indicates that hippocampal activity contributes to sensorimotor gating, suggesting intact PPI after permanent hippocampal lesions to reflect compensatory processes. The data are discussed with respect to hippocampal dysfunction in schizophrenia.