Amygdala lesions block the amnestic effects of diazepam

This experiment examined the effects of pre-training systemic injections of the benzodiazepine (BZ) diazepam (DZP) on learning and retention of an inhibitory avoidance response in rats with bilateral lesions of the amygdaloid complex (AC) induced by intra-amygdala injections of the excitotoxin N-methyl-D-aspartic acid (NMDA). Unoperated, sham-operated and AC-lesioned rats received i.p. injections of DZP (1.0 or 2.0 mg/kg) or vehicle 30 min prior to training in a continuous multiple-trial inhibitory avoidance task. Retention was tested 48 h later. The acquisition and retention of the AC-lesioned rats were impaired, relative to that of the unoperated and sham controls. In the unoperated and sham controls, DZP impaired retention but did not affect acquisition. In contrast, in animals with AC lesions, DZP did not affect either acquisition or retention. These findings suggest that the amnestic effects of DZP are mediated, at least in part, through influences involving the AC.     

GABAergic neurons of the rat dorsal hippocampus express muscarinic acetylcholine receptors

The expression of muscarinic acetylcholine receptors (mAChRs) in glutamic acid decarboxylase (GAD)-positive cells in the different strata of CA1, CA3, and the dentate gyrus (DG) of the dorsal hippocampus is examined by way of quantitative immunofluorescent double labeling employing M35, the monoclonal antibody raised against purified mAChR protein. Of all GAD-positive neurons, 97.5% express mAChRs. Conversely, 92.9% of the muscarinic cholinoceptive nonpyramidal neurons express GAD. These results indicate that the vast majority of the γ-aminobutyric acid (GABA)ergic neurons express mAChRs. In addition to GAD, parvalbumin (PARV) and somatostatin (SOM) are two neurochemical substances notably expressed in GABAergic neurons. In order to examine whether the entire muscarinic cholinoceptive nonpyramidal cell group can be characterized by these three GABAergic markers, a cocktail of GAD, PARV, and SOM was used in a fluorescent double-labeling experiment with M35. These results show that 97.2% of all muscarinic cholinoceptive nonpyramidal neurons can be neurochemically characterized by the content of GAD, PARV, and SOM. In conclusion, nearly all GABAergic cells express mAChRs and, conversely, virtually the entire muscarinic cholinoceptive nonpyramidal cell group belongs to the GABAergic cell population. This study, therefore, provides anatomical evidence for an extensive neuronal connectivity of the hippocampal muscarinic cholinoceptive nonpyramidal system and the inhibitory GABAergic circuitry.     

Amygdala kindling effects on sleep and memory in rats

Sleep disturbances accompany the development of amygdaloid-kindled seizures in cats. Some of these sleep deficits resemble those seen in aged rats; these latter changes in sleep patterns are correlated with memory impairments in the aged animals. In the present study, we examined the hypothesis that sleep deficits after kindling may be related to memory impairments. Rats were kindled for 4 weeks (2-2.5 weeks after stage 5 seizures) and were then allowed a one week recovery period. Sleep patterns were assessed through-out the kindling and recovery periods. The animals were then trained on an inhibitory avoidance apparatus and tested for retention 24 h later. Only transient sleep changes occurred during the development of kindling (to stage 5 seizures). However, continued kindling resulted in significant reductions in several sleep measures which remained depressed for at least one week after the termination of the kindling trials. As a group, kindled rats were impaired in retention of the inhibitory avoidance learned response. In kindled animals, retention performance was significantly correlated with total paradoxical sleep, the ratio of paradoxical/total sleep, and paradoxical sleep, the ratio of paradoxical/total sleep, and paradoxical sleep bout duration. These correlations are consistent with the view that deficits in paradoxical sleep may be related to deficits in some forms of memory.     

Effects of amygdala lesions on dorsal hippocampus kindling in rats

In two experiments, bilateral amygdala lesions were shown to facilitate the rate of kindling from the dorsal hippocampus. This facilitation was produced equally by an amygdala lesion ipsilateral to the kindled focus, whereas a lesion contralateral to the focus was ineffective. An interesting negative correlation emerged between the kindling rate and latency to onset of forelimb clonus, i.e., the faster the kindling, the longer the convulsion latencies.     

Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse

Duchenne muscular dystrophy (DMD) is characterized by variable alterations of the dystrophin gene and by muscle weakness and cognitive impairment. We postulated an association between cognitive impairment and architectural changes of the hippocampal GABAergic system. We investigated a major subpopulation of GABAergic neurons, the parvalbumin-immunopositive (PV-I) cells, in the dorsal hippocampus of the mdx mouse, an acknowledged model of DMD. PV-I neurons were quantified and their distribution was compared in CA1, CA2, CA3, and dentate gyrus in wild-type and mdx mice. The cell morphology and topography of PV-I neurons were maintained. Conversely, the number of PV-I neurons was significantly increased in the mdx mouse. The percent increase of PV-I neurons was from 45% for CA2, up to 125% for the dentate gyrus. In addition, the increased parvalbumin content in the mdx hippocampus was confirmed by Western blot. A change in the hippocampus processing abilities is the expected functional counterpart of the modification displayed by PV-I GABAergic neurons. Altered hippocampal functionality can be responsible for part of the cognitive impairment in DMD.     

Tetrodotoxin infusions into the dorsal hippocampus block non-locomotor place recognition

The hippocampus is critical for navigation in an open field. One component of this navigation requires the subject to recognize the target place using distal cues. The experiments presented in this report tested whether blocking hippocampal function would impair open field place recognition. Hungry rats were trained to press a lever on a feeder for food. In Experiment 1, they were passively transported with the feeder along a circular trajectory. Lever pressing was reinforced only if the feeder was passing through a 60 degrees -wide sector. Thus, rats preferentially lever pressed in the vicinity of the reward sector indicating that they recognized its location. Tetrodotoxin (TTX) infusions aimed at the dorsal hippocampi caused rats to substantially increase lever pressing with no preference for any region. The aim of Experiment 2 was to determine whether the TTX injections caused a loss of place recognition or a general increase of lever pressing. A separate group of rats was conditioned in a stationary apparatus to press the lever in response to a light. The TTX injections did not abolish preferential lever pressing in response to light. Lever pressing increased less than half as much as the TTX-induced increase in Experiment 1. When these animals with functional hippocampi could not determine the rewarded period because the light was always off, lever pressing increased much more and was similar to the TTX-induced increase in Experiment 1. We conclude that the TTX inactivation of the hippocampi impaired the ability to recognize the reward place.     

Differential effects of zinc on glutamatergic and GABAergic neurotransmitter systems in the hippocampus

Approximately 10% of total zinc in the brain exists in synaptic vesicles of glutamatergic neurons; however, the function of vesicular zinc is poorly understood. The presynaptic action of zinc against excitatory and inhibitory neurotransmission was studied in rat hippocampus using in vivo microdialysis. When the hippocampal CA3 region was perfused with 10-300 microM ZnCl(2), the level of glutamate in the perfusate was decreased, whereas the level of gamma-aminobutyric acid (GABA) was increased. Chelation of endogenous zinc with CaEDTA increased the glutamate level in the perfusate but decreased the GABA level, suggesting that zinc released into the synaptic cleft acts differentially on glutamatergic and GABAergic neurons in the CA3 region. The increase of GABA level by zinc was antagonized by 2,3-dioxo-6-nitro-1,2.3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide (NBQX), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors, but not affected by MK801, an antagonist of N-methyl-D-aspartate (NMDA) receptors, and verapamil, a blocker of voltage-dependent calcium channels. The present study suggests that zinc enhances GABA release via potentiation of AMPA/kainate receptors in the CA3 region, followed by a decrease in presynaptic glutamate release in the same region. Zinc seems to be an inhibitory neuromodulator of glutamate release.     

Different implications of the dorsal and ventral hippocampus on contextual memory retrieval after stress

This study assessed the relative contributions of dorsal (dHPC) and ventral (vHPC) hippocampus regions in mediating the rapid effects of an acute stress on contextual memory retrieval. Indeed, we previously showed that an acute stress (3 electric footschocks; 0.9 mA each) delivered 15 min before the 24 h‐test inversed the memory retrieval pattern in a contextual discrimination task. Specifically, mice learned in a four‐hole board two successive discriminations (D1 and D2) varying by the color and texture of the floor. Twenty‐four hours later, nonstressed animals remembered accurately D1 but not D2 whereas stressed mice showed an opposite memory retrieval pattern, D2 being more accurately remembered than D1. We showed here that, at the time of memory testing in that task, stressed animals exhibited no significant changes neither in pCREB activity nor in the time‐course evolution of corticosterone into the vHPC; in contrast, a significant decrease in pCREB activity and a significant increase in corticosterone were observed in the dHPC as compared to nonstressed mice. Moreover, local infusion of the anesthetic lidocaine into the vHPC 15 min before the onset of the stressor did not modify the memory retrieval pattern in nonstress and stress conditions whereas lidocaine infusion into the dHPC induced in nonstressed mice an memory retrieval pattern similar to that observed in stressed animals. The overall set of data shows that memory retrieval in nonstress condition involved primarily the dHPC and that the inversion of memory retrieval pattern after stress is linked to a dHPC but not vHPC dysfunction.     

Differential effects of interferon on ventromedial hypothalamus and dorsal hippocampus

Three incremental doses of recombinant alpha-interferon (IF) were applied iontophoretically to hippocampal and hypothalamic cells. IF produced a dose-dependent long-lasting excitation in hippocampal neurons, whereas, in the hypothalamus alpha-IF elicited biphasic responses. The highest IF currents induced changes in the amplitude of the action potentials on both structures. Our observations suggest that IF could have a selective effect on the specific areas studied.     

Involvement of the amygdala GABAergic system in the modulation of memory storage

These experiments examined the involvement of the intrinsic GABAergic system of the amygdaloid complex in the modulation of memory storage. Rats were chronically implanted with bilateral cannulae in the amygdala, trained in an inhibitory avoidance task, and given post-training bilateral intra-amygdala injections of either the GABA receptor antagonist bicuculline methiodide (BMI) (0.1-1.0 nmol) or the GABAA receptor agonist muscimol (0.001-0.1 nmol). As indicated by performance on a 48 h retention test, BMI enhanced retention of the inhibitory avoidance conditioning, while muscimol impaired retention. The memory-enhancement obtained with BMI (0.1 nmol) was produced by a dose lower than that necessary to induce convulsions. Post-training injections of BMI did not affect retention when injected into the caudate-putamen dorsal to the amygdala. These results suggest that the amygdaloid GABAergic system is involved in the modulation of memory storage.     

Effects of lesions to the dorsal and ventral hippocampus on defensive behaviors in rats

This study investigated the role of the hippocampus in both unconditioned and conditioned defensive behaviors by examining the effects of pretraining ibotenic acid lesions to the dorsal and ventral hippocampus in male Long-Evans hooded rats exposed to three types of threat stimuli: cat-odor, a live cat and footshock. Defensive behaviors were assessed during exposure to cat-odor and a live cat, and immediately following the presentation of footshock. Conditioned defensive behaviors were also assessed in each context 24 h after initial threat exposure. During both unconditioned and conditioned trials, dorsal hippocampal lesions failed to significantly alter any behavioral measure in each test of defense. In contrast, ventral hippocampal lesions significantly reduced unconditioned defensive behaviors during exposure to cat-odor without producing any observable effects during cat exposure. Furthermore, ventral lesions significantly attenuated conditioned defensive behaviors following the administration of footshock and during re-exposure to each context. These results suggest a specific role for the ventral, not dorsal, hippocampus in modulating anxiety-like behaviors in certain animal models of defense.     

Effects of medial and dorsal cortex lesions on spatial memory in lizards

In mammals and birds, the hippocampus is a major learning and memory center that plays a prominent role in spatial memory, the use of distal cues to guide navigation. The role of reptilian hippocampal homologues, the medial and dorsal cortex, in spatial memory has not been thoroughly investigated. The medial and dorsal cortex of reptiles is known to play a role in learning both tasks that are hippocampally dependent and tasks that are not hippocampally dependent in mammals and birds. In order to examine the specific role of the medial and dorsal cortex in spatial memory, we trained medial cortex, dorsal cortex, and sham lesioned Cnemidophorus inornatus lizards to locate the one heated rock of four identical rocks spaced evenly around the perimeter of a circular, sand filled, arena in a cool room. We used probe trials to examine the strategies used by lizards to locate the goal. Medial cortex lesions and dorsal cortex lesions slowed acquisition and altered the strategies used to locate the goal. However, none of the lizards adopted a spatial strategy to locate the goal suggesting that the dorsal cortex and medial cortex are involved in using non-spatial strategies for navigation.     

Partial unilateral inactivation of the dorsal hippocampus impairs spatial memory in the MWM

The hippocampus is one of the more widely studied structures related with spatial memory. In this study, we assessed the effect of unilateral inactivation of the dorsal hippocampus with tetrodotoxin (TTX) on the performance displayed by Wistar rats in the spatial version of the Morris water maze. In experiment 1, we injected into the dorsal hippocampus in two different groups of rats 1 microl of saline solution or 5 ng of TTX in 1 microl of saline each day immediately after the training during four consecutive days. This procedure blocked consolidation and impaired spatial memory in the TTX group. In experiment 2, a new group of subjects was trained in the Morris water maze for 8 days and was administered 1 microl of saline on day 7 (saline session) and TTX on day 8 (TTX session) into the dorsal hippocampus 40 min before the training. Only the treatment with TTX altered the retrieval of memories. These experiments showed that unilateral interventions on the dorsal hippocampus can affect consolidation as well as retrieval of well-established spatial memories.     

The effects of study task on prestimulus subsequent memory effects in the hippocampus

Functional magnetic resonance imaging (fMRI) was employed to examine the effects of a study task manipulation on pre‐stimulus activity in the hippocampus predictive of later successful recollection. Eighteen young participants were scanned while making either animacy or syllable judgments on visually presented study words. Cues presented before each word denoted which judgment should be made. Following the study phase, a surprise recognition memory test was administered in which each test item had to be endorsed as “Remembered,” “Known,” or “New.” As expected, “deep” animacy judgments led to better memory for study items than did “shallow” syllable judgments. In both study tasks, pre‐stimulus subsequent recollection effects were evident in the interval between the cue and the study item in bilateral anterior hippocampus. However, the direction of the effects differed according to the study task: whereas pre‐stimulus hippocampal activity on animacy trials was greater for later recollected items than items judged old on the basis of familiarity (replicating prior findings), these effects reversed for syllable trials. We propose that the direction of pre‐stimulus hippocampal subsequent memory effects depends on whether an optimal pre‐stimulus task set facilitates study processing that is conducive or unconducive to the formation of contextually rich episodic memories. © 2015 Wiley Periodicals, Inc.     

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval,and combining them attenuates the acquisition rate of spatial reference memory

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over‐generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.     

Dopamine-antagonistic, anticholinergic, and GABAergic effects on declarative and procedural memory functions

Declarative and procedural memory functions are related to dissociable neuroanatomic substrates. In the present study differential effects of pharmacologically induced changes in dopaminergic, GABAergic, and cholinergic activity in the brain on declarative (object and face recognition, immediate and delayed word recall) and procedural memory processes (compensatory tracking) were investigated. In a double-blind design, either 3 mg of haloperidol, 11 mg of midazolam, 1 mg of scopolamine, or placebo were administered to 80 healthy volunteers randomly assigned to one of the four drug conditions. Although all three drugs produced a detrimental effect on immediate and delayed word recall, recall performance was substantially more impaired by the benzodiazepine midazolam than by either haloperidol or scopolamine. While recognition of faces was affected by neither of the drugs, performance on object recognition was significantly decreased by midazolam as compared to placebo. Procedural learning was markedly impaired by all drugs but, again, the observed effect was most pronounced with midazolam. Additional analyses of measures of subjective activation, cortical arousal, and psychomotor performance argued against the assumption that the observed memory-impairing effects were secondary to drug-induced sedation. The overall pattern of results revealed that memory processes are much more susceptible to changes in GABAergic than in dopaminergic or cholinergic neurotransmitter activity. Furthermore, the present findings point to the conclusion that the modulating effects of dopaminergic, GABAergic, and cholinergic neurotransmitter systems on declarative and procedural memory functions are less specific than suggested by neuropsychological studies in patients.     

针药治疗抑郁症过程中患者海马、额叶代谢的变化

目的：对正常志愿者、抑郁症患者脑海马、前额叶进行1H-MRS分析,探讨治疗前后脑内代谢物质的变化特点。方法：将75例轻、中度抑郁症患者随机分为西药组（A组）、电针组（B组）、针药组（C组）,采用GE EXCITE II Signa 3.0T磁共振系统,PROBE-J序列进行单体素采集,感兴趣区分别置于左、右两侧海马和额叶。比较正常志愿者与3组患者治疗前后N－乙酰天门冬氨酸/胆碱（NAA/Cho）、N－乙酰天门冬氨酸/肌酸（NAA/Cr）和胆碱/肌酸（Cho/ Cr）值的差异。结果：治疗前三组患者双侧海马的NAA/Cr值较对照组减低,治疗后B组双侧海马、C组右侧海马的NAA/Cr值较治疗前增高（P<0.05）,C组左侧海马的NAA/Cr值较治疗前明显增高（P<0.01）。治疗前三组患者双侧额叶的Cho/ Cr值较对照组增高（P<0.05）,治疗后A组、B组双侧额叶的Cho/ Cr值较治疗前减低（P<0.05）,C组双侧额叶的Cho/ Cr值较治疗前明显减低（P<0.01）。结论：抑郁症患者双侧额叶、海马与正常成人相应部位的代谢物浓度存在差异,三种方案干预前后抑郁症患者脑功能活动各项指标的改变表明电针可通过多途径改善抑郁,而百优解的作用途径单一。     

The effects of dorsal bundle lesions on serial and trace conditioning

The performance of rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) was compared with that of sham-operated control animals under two behavioural conditions. Animals with DB lesions were slower than controls to acquire a classically-conditioned emotional response (conditioned suppression) with a trace interval interposed between the clicker conditioned stimulus (CS) and the shock reinforcer. However, if the latter half of the trace interval was filled by a second stimulus, a light, the DB-lesioned animals acquired conditioned suppression to the clicker faster than did controls under the same conditions. These results are discussed in terms of the attentional theory of DB function.