Stimulation Of Ventral Hippocampus Research Articles

Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid.

Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation in vivo and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of α7-nicotinic acetylcholine receptors (α7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an α7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABAAR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions.SIGNIFICANCE STATEMENT Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory-inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.

Developmental Disruption of Gamma-Aminobutyric Acid Function in the Medial Prefrontal Cortex by Noncontingent Cocaine Exposure During Early Adolescence

Drug experimentation during adolescence is associated with increased risk of drug addiction relative to any other age group. To further understand the neurobiology underlying such liability, we investigate how early adolescent cocaine experience impacts medial prefrontal cortex (mPFC) network function in adulthood. A noncontingent administration paradigm was used to assess the impact of early adolescent cocaine treatment (rats; postnatal days [PD] 35-40) on the overall inhibitory regulation of mPFC activity in adulthood (PD 65-75) by means of histochemical and in vivo electrophysiological measures combined with pharmacologic manipulations. Cocaine exposure during early adolescence yields a distinctive hypermetabolic prefrontal cortex state that was not observed in adult-treated rats (PD 75-80). Local field potential recordings revealed that early adolescent cocaine exposure is associated with an attenuation of mPFC gamma-aminobutyric acid (GABA)ergic inhibition evoked by ventral hippocampal stimulation at beta and gamma frequencies that endures throughout adulthood. Such cocaine-induced mPFC disinhibition was not observed in adult-exposed animals. Furthermore, the normal developmental upregulation of parvalbumin immunoreactivity observed in the mPFC from PD 35 to PD 65 is lacking following early adolescent cocaine treatment. Our data indicate that repeated cocaine exposure during early adolescence can elicit a state of mPFC disinhibition resulting from a functional impairment of the local prefrontal GABAergic network that endures through adulthood. A lack of acquisition of prefrontal GABAergic function during adolescence could trigger long-term deficits in the mPFC that may increase the susceptibility for the onset of substance abuse and related psychiatric disorders.

Periadolescent exposure to the NMDA receptor antagonist MK-801 impairs the functional maturation of local GABAergic circuits in the adult prefrontal cortex.

A developmental disruption of prefrontal cortical inhibitory circuits is thought to contribute to the adolescent onset of cognitive deficits observed in schizophrenia. However, the developmental mechanisms underlying such a disruption remain elusive. The goal of this study is to examine how repeated exposure to the NMDA receptor antagonist dizocilpine maleate (MK-801) during periadolescence [from postnatal day 35 (P35) to P40] impacts the normative development of local prefrontal network response in rats. In vivo electrophysiological analyses revealed that MK-801 administration during periadolescence elicits an enduring disinhibited prefrontal local field potential (LFP) response to ventral hippocampal stimulation at 20 Hz (beta) and 40 Hz (gamma) in adulthood (P65-P85). Such a disinhibition was not observed when MK-801 was given during adulthood, indicating that the periadolescent transition is indeed a sensitive period for the functional maturation of prefrontal inhibitory control. Accordingly, the pattern of prefrontal LFP disinhibition induced by periadolescent MK-801 treatment resembles that observed in the normal P30-P40 prefrontal cortex (PFC). Additional pharmacological manipulations revealed that these developmentally immature prefrontal responses can be mimicked by single microinfusion of the GABA(A) receptor antagonist picrotoxin into the normal adult PFC. Importantly, acute administration of the GABA(A)-positive allosteric modulator Indiplon into the PFC reversed the prefrontal disinhibitory state induced by periadolescent MK-801 to normal levels. Together, these results indicate a critical role of NMDA receptors in regulating the periadolescent maturation of GABAergic networks in the PFC and that pharmacologically induced augmentation of local GABA(A)-receptor-mediated transmission is sufficient to overcome the disinhibitory prefrontal state associated with the periadolescent MK-801 exposure.

Neural circuits engaged in ventral hippocampal modulation of dopamine function in medial prefrontal cortex and ventral striatum

Dopamine (DA) transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) is crucial for various cognitive processes. However, our understanding of the regulation of DA efflux by glutamatergic afferents to these areas is incomplete. Using microdialysis in freely moving rats, we provide evidence in the present study that brief stimulation (20 Hz, 10 s) of the ventral hippocampus potently increases DA efflux in the mPFC, NAc, and ventral tegmental area for 30-40 min. Subsequent experiments show that the stimulation-evoked increase in DA efflux in the mPFC depends on local activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate, but not N-methyl-D-aspartate, receptors in the mPFC. Additionally, neural activity and ionotropic glutamate receptor activation in the ventral tegmental area are necessary for ventral hippocampal stimulation to increase mPFC DA efflux. Blocking neural activity or ionotropic glutamate receptors in the ventral tegmental area also attenuated the stimulation-evoked increase in DA efflux in the NAc. Evidence in support of a role for the mPFC in the stimulation-evoked increase in NAc DA was not obtained. Taken together, these observations highlight the important role of the ventral hippocampus in modulating forebrain DA efflux via separate neural circuits.

Electrical stimulation of dorsal, but not ventral hippocampus reduces behavioral defense in the elevated plus maze and shock-probe burying test in rats

Recent evidence indicates that the hippocampus contributes to the control of defensive behaviors in rodents. Here, electrical stimulation (1s, 60Hz) of the rat dorsal hippocampus inhibited defense in the elevated plus maze (increased open arm exploration) and shock-probe burying test (reduced burying duration), while ventral hippocampal stimulation had no effects. Thus, the dorsal hippocampus may play an important role in modulating a range of defensive strategies.

Lesions of the rat piriform cortex prevent long-lasting sensorimotor gating deficits induced by stimulation of the ventral hippocampus

Prepulse inhibition (PPI) is a cross-species operational measure of sensorimotor gating. Reduced PPI is found in schizophrenics and can be induced experimentally in rats. Stimulation of the rat ventral hippocampus (VH) with N-methyl- d-aspartate (NMDA) results in long-lasting PPI deficits (carry-over effect). Since we have previously shown that this carry-over effect was accompanied by increased expression of c-Fos in the piriform cortex (PIR), we here tested the effects of lesions of the PIR on PPI after stimulation of the VH. PIR lesioned rats still showed disruption of PPI after injection of NMDA into the VH. However, the carry-over effect observed in controls was prevented by PIR lesions. These data suggest that the PIR is important for long-lasting alterations in brain functioning leading to impaired sensorimotor gating.

Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D 1 and D 2 receptors

Numerous studies have suggested that excitatory projections from the ventral hippocampus to the nucleus accumbens modulate locomotor activity in rats. Furthermore, the ability of ventral hippocampal neurons to alter locomotor activity may involve the dense dopaminergic innervation found in the nucleus accumbens. The purpose of this study was to: (i) more fully characterize the locomotor effects of acute alterations in ventral hippocampal activity; (ii) ascertain the influence of dopamine agonists and antagonists on locomotor changes produced by altered ventral hippocampal activity; and (iii) use immediate early gene induction to determine whether dopamine antagonists alter the response of nucleus accumbens neurons to ventral hippocampal stimulation. By comparing a variety of excitatory amino acid agonists, it was found that ventral hippocampal infusion of N-methyl- d-aspartate elevated locomotor activity in a subconvulsive manner, while other excitatory amino acid receptor agonists did not. Inactivation of the ventral hippocampus achieved by lidocaine infusion did not suppress ongoing locomotor activity, nor did it affect amphetamine-induced increases in locomotor activity. Increases in locomotor activity induced by ventral hippocampal N-methyl- d-aspartate infusion were blocked by systemic administration of haloperidol (a D 2 receptor antagonist), SCH-23390 (a D 1 receptor antagonist) or reserpine. Cellular expression of the protein product of the immediate early gene, c-fos, was dramatically increased in the nucleus accumbens shell after ventral hippocampal N-methyl- d-aspartate infusion, and haloperidol, SCH-23390 and reserpine attenuated this effect. These results suggest that the increases, but not decreases, in ventral hippocampal activity have a measurable effect on ongoing rates of locomotion, and that this effect requires both D 1 and D 2 receptors. Moreover, the studies of Fos expression suggest that dopamine receptor antagonists attenuate neuronal responses to ventral hippocampal stimulation within the nucleus accumbens, a brain region important in the generation and maintenance of locomotor activity.

Haloperidol Blocks Increased Locomotor Activity Elicited by Carbachol Infusion Into the Ventral Hippocampal Formation

Previous studies have demonstrated that stimulation of the ventral hippocampal (VH) formation (including the ventral CA1 and subicular areas) elicits increased locomotor activity in rats. The locomotor-activating effects of VH stimulation have been hypothesized to be mediated via hippocampal output to cortical and subcortical dopamine (DA) systems. This study examined whether increased locomotor activity produced by VH stimulation was blocked by pretreatment with a DA receptor antagonist, and whether DA metabolism in subdivisions of the nucleus accumbens, caudate-putamen, and prefrontal cortex was elevated by VH stimulation. Stimulation of the VH (defined as the ventral CA1 and its borders, ventral subiculum, and entorhinal cortex) with the cholinergic agonist carbachol was found to elevate locomotor activity, while pretreatment with the D 2 receptor antagonist haloperidol blocked this effect. Stimulation of the VH did not alter DA metabolism (i.e., ratio of the DA metabolites DOPAC or HVA/DA) in any of the brain regions studied. These results indicate that the increased locomotor activity elicited by VH stimulation is not associated with dramatic increases in DA metabolism, but that it does require tonic activation of D 2 receptors.

An analysis of the mechanisms underlying hippocampal control of hypothalamically-elicited aggression in the cat

An experiment was performed to determine the role of the hippocampal formation in the regulation of quiet biting attack behavior elicited from electrical stimulation of the hypothalamus. The results showed clearly that stimulation of the dorsal hippocampus resulted in an increased latency to quiet biting attack and that ventral hippocampal stimulation resulted in a decreased latency to quiet biting attack. In addition, the results indicate that those sites in the ventral hippocampal formation from which facilitation of attack can be produced are linked to sensory mechanisms associated with trigeminal reflexes established during hypothalamic stimulation inasmuch as stimulation of these sites increase the lateral extent of the effective sensory field of the lipline. No effect was observed upon a motor component of the jaw-opening response — the latency to jaw-opening — during ventral hippocampal stimulation. In contrast, no effects were observed upon either sensory or motor components of the hypothalamically-elicited jaw-opening response as a result of stimulation of dorsal hippocampal sites. Deoxyglucose autoradiography revealed that the major effect of stimulation of modulatory sites in both the dorsal and ventral hippocampal formation was exerted upon the lateral septal nucleus. Thus, it is proposed that hippocampal modulation of hypothalamically-elicited quiet biting attack is mediated primarily through the lateral septal nucleus.

Tubero-infundibular dopamine neurons and the secretion of luteinizing hormone and prolactin: extrahypothalamic influences, interaction with cholinergic systems and the effect of urethane anesthesia

In ovariectomized, estrogen-progesterone-pretreated rats, the fluorescence intensity of the cell bodies of tubero-infundibular dopamine (DA) neurons — as detected by histochemical microfluorimetry — increased rapidly after unilateral stimulation (10 min) of arcuate nucleus, medial preoptic area, medial amygdaloid nucleus, nucleus of diagonal tract, bed nucleus of stria terminalis or ventromedial midbrain tegmentum. After catecholamine synthesis inhibition, ventral hippocampal stimulation (30 min) retarded the depletion of DA neurons and thus differed in its effect from preoptic stimulation. Atropine reduced the intensity response to stimulation in all the areas where its action was studied, except for the arcuate nucleus where the DA neurons are mainly localized. Its effect was dose-dependent (0.4–10 mg/kg). Methylatropine, which crosses the blood-brain barrier in much lower amounts, remained ineffective. An increase in the variance of the DA neuron population was noted after atropine, suggesting a certain functional heterogeneity. The changes in fluorescence intensity were correlated with the serum levels of luteinizing hormone (LH) and prolactin. Response patterns depended upon site of stimulation and treatment. With preoptic stimulation, the intensity response was accompanied by a rise in LH and no change in prolactin; atropine caused a reduction of intensity change and LH rise together with an increase in prolactin. With stimulation sites outside the preoptico-tuberal axis, such as medial amygdala, stimulation and atropine affected the intensity in a similar way, yet LH increased only after atropine while prolactin levels were elevated with or without atropine. Urethane anesthesia probably contributed to the differentiation of neuroendocrine responses, its effect being partly counteracted by atropine. Thus, short-term influences depending in part on cholinergic activity reach the tubero-infundibular DA neurons from various extrahypothalamic areas. The accompanying patterns of hormone secretion probably result from an interaction of these neurons with other systems projecting to the median eminence.

Single unit analysis of the hippocampal projections to the septum in the cat

The purpose of this study was to map the hippocampal efferent projections to the septum and to determine the synaptic organization of the hippocampal-septal system in the cat. Single unit responses were recorded in the septum with tungsten microelectrodes following electrical stimulation of the dorsal or ventral hippocampus in the anesthetized cat. Dorsal hippocampal stimulation produced excitatory unit driving at short latencies in the medial septum while ventral hippocampal stimulation produced short latency excitation in the lateral septum. The excitatory phase was invariably followed by a period of inhibition. Inhibition without a prior excitatory phase was seen in widespread regions of the septum upon either dorsal or ventral hippocampal stimulation. It was concluded that efferents from the dorsal and ventral hippocampus terminate in a topographic manner in the medial and lateral septum, respectively, and have excitatory effects upon these neurons as well. An interneuronal inhibitory network capable of influencing large regions of the septum was suggested from the data.

The spread of after-discharge from stimulation of the rhinencephalon in the cat

1. 1. The spread of after-discharge following electrical stimulation of the dorsal and ventral hippocampus, septum, basal and lateral amygdaloid nuclei, and the anterior sigmoid gyrus has been studied in locally anesthetized cats and in animals anesthetized with Dial. 2. 2. From each stimulated focus after-discharge was found to spread diffusely to subcortical and paleocortical areas, but the overall epileptoid response varied in character and some areas remained negative. Propagation of after-discharge to the dorsolateral isocortex was less diffuse than that to subcortical brain levels. 3. 3. Following stimulation of each area investigated, rhythmic after-discharge of high amplitude was recorded from certain brain structures and these corresponded with the same areas that fired at liminal stimulation of the same foci in animals anesthetized with Dial. These were predominantly rhinencephalic and hypothalamic nuclei when rhinencephalic areas were stimulated and structures of the pyramidal and extrapyramidal systems when the anterior sigmoid gyrus was stimulated. 4. 4. The medial geniculate body, ventrolateral reticular formation and associational thalamic nuclei responded prominently to each of the rhinencephalic structures stimulated. 5. 5. After-discharge of certain areas appeared to be distinctive, such as: activation of the ventral thalamus following ventral hippocampal stimulation; the intralaminar thalamic nuclei after dorsal hippocampal stimulation; the sensorimotor cortex after basal amygdaloid stimulation; and superior colliculus and lateral geniculate nucleus after stimulation of the septum. 6. 6. It is concluded that each area stimulated has a pattern of ictal projection to the subcortex, paleo- and juxtallocortex and neocortex that is sufficiently distinctive, but that there is considerable overlap in the main projection areas of each rhinencephalic focus. There is a strong contrast between the propagation pattern of after-discharge from the rhinencephalon and that originating in the anterior sigmoid gyrus. 7. 7. The possible correlation of certain features of rhinencephalic after-discharge with autonomic and behavioral effects generally known to follow rhinencephalic stimulation or ablation, and with clinical effects of psychomotor epilepsy have been discussed.