Stimulation Of Amygdala Research Articles

Amygdalofugal modulation of the vago-vagal gastric motor reflex in rat

In experiments on urethane anaesthetized rats the influence of electrical stimulation of the central nucleus of the amygdala (CNA) on gastric motility and activity of gastric-related neurons of the dorsal vagal complex was studied. Stimulation of the CNA effected spontaneous gastric motility and caused both excitatory and inhibitory changes of vagal-induced gastric relaxation. The most significant effects, mainly inhibitory, were observed under stimulation of the medial CNA. This amygdaloid area was found to influence activity of gastric-related neurons of the dorsal vagal complex. Excitatory and inhibitory changes of their vagal-induced responses under the amygdala stimulation manifested as general modulation of all phases of the reaction or selective modulation of some of them. These mechanisms may lie at the base of amygdalofugal modulation of gastric reflex activity.

Potential role of medullary raphe-spinal neurons in cutaneous vasoconstriction: an in vivo electrophysiological study.

In rabbits, raphe magnus/pallidus neurons form a link in the CNS pathway regulating changes in cutaneous blood flow elicited by nociceptive stimulation and activation of the central nucleus of the amygdala. To characterize relevant raphe-spinal neurons, we performed extracellular recordings from the rostral medullary raphe nuclei in anesthetized, paralyzed, mechanically ventilated rabbits. All studied neurons were antidromically activated from the dorsolateral funiculus of the spinal cord (C(8)-T(2)). Of 129 studied neurons, 40% were silent. The remaining neurons discharged spontaneously at 0.3-29 Hz. Nociceptive stimulation (lip squeeze with pliers) excited 63 (49%), inhibited 9 (7%), and did not affect 57 (44%) neurons. The same stimulation also elicited falls in ear pinna blood flow. In neurons activated by the stimulation, the increase in discharge preceded the fall in flow. Electrical stimulation of the spinal trigeminal tract excited 61/63 nociception-activated neurons [onset latencies range: 6-75 ms, mean: 28 +/- 3 (SE) ms], inhibited 9/9 nociception-inhibited neurons (onset latencies range: 9-85 ms, mean: 32 +/- 10 ms), and failed to affect 55/57 neurons insensitive to nociceptive stimulation. Neurons insensitive to nociceptive/trigeminal stimulation were also insensitive to nonnociceptive tactile stimulation and to electrical stimulation of the amygdala. They were either silent (32/45) or discharged regularly at low frequencies. They possessed long-duration action potentials (1.26 +/- 0.08 ms) and slow-conducting axons (6.0 +/- 0.5 m/s). These neurons may be serotonergic raphe-spinal cells. They do not appear to be involved in nociceptive-related cutaneous vascular control. Of the 63 neurons sensitive to nociceptive and trigeminal tract stimulation, 35 also responded to tactile stimulation (wide receptive field). These neurons possessed short action potentials (0.80 +/- 0.03 ms) and fast-conducting axons (30.3 +/- 3.1 m/s). In this subpopulation, electrical stimulation of the amygdala activated nearly all neurons tested (10/12), with a mean onset latency of 34 +/- 3 ms. The remaining 28 neurons sensitive to nociceptive and trigeminal stimulation did not respond to tactile stimuli and were mainly unaffected by amygdala stimulation. It may be that fast-conducting raphe-spinal neurons, with wide multimodal receptive fields and with input from the central nucleus of the amygdala, constitute the bulbo-spinal link in the CNS pathway regulating cutaneous blood flow in response to nociceptive and alerting stimuli.

Long-term depression in the basolateral amygdala of the mouse involves the activation of interneurons

Long-term depression (LTD) in the basolateral amygdala, following low frequency stimulation (1 Hz/900 pulses) of the lateral amygdala, was studied in an in vitro slice preparation of 2–3 weeks and 2–4 months old mice. Whole-cell patch-clamp recordings of neurons, visualized by means of infrared videomicroscopy, and extracellular field potential recordings were performed. Loading single neurons with the calcium chelator BAPTA (30 mM) did not reduce the excitatory postsynaptic currents following low frequency stimulation. However, buffering presynaptic calcium with BAPTA-AM, and application of the specific Ca 2+/calmodulin-stimulated protein kinase II antagonist KN-62 (1-[ N, O-bis(5-isoquinoline sulfonyl)- N-methyl- L-tyrosyl]-4-phenylpiperizine), blocked low frequency stimulation-induced LTD. The induction of LTD was reduced by the competitive N-methyl- D-aspartate receptor antagonist D-(−)-2-amino-5-phosphonopentanoic acid (50 μM), and blocked by the metabotropic glutamate receptor antagonist (−)-amino-4-carboxy-methyl-phenylacetic acid (1 mM), and by 5-hydroxytryptamine (5-HT; 30 μM) via the activation of 5-HT 1A receptors. Also blocking GABA A receptor-mediated synaptic transmission with bicuculline (10 μM) or picrotoxin (20 μM) reduced the induction of LTD. Visually and electrophysiologically identified interneurons in slices from 2 weeks old mice, expressed in contrast to adult mice (2–4 months), pronounced LTD. Principal neurons showed only weak LTD after low frequency stimulation. A synopsis of these findings suggests a pivotal role of GABAergic interneurons and serotonergic afferents in the induction of LTD in the basolateral nucleus of the amygdala.

Stimulation of the medial amygdala enhances medial preoptic dopamine release: implications for male rat sexual behavior

Increased dopamine (DA) in the medial preoptic area (MPOA) facilitates male sexual behavior. A major source of innervation to the MPOA is the medial amygdala (MeA). We now report that chemical stimulation of the MeA enhanced levels of extracellular MPOA DA in anesthetized male rats. These results suggest that DA activity in the MPOA can be regulated by input from the MeA to the MPOA.

Enhanced frontal cortex activation in rats by convergent amygdaloid and noxious sensory signals.

The modulation of frontal cortical EEG activation to noxious somatosensory (tail pressure) and olfactory (acetone) stimulation by the basal amygdala was examined in urethane-anesthetized rats. Mild tail pressure produced no EEG activation, while acetone (sniffed by freely breathing rats or drawn across the olfactory epithelium in tracheotomized rats) produced a moderate suppression of large-amplitude synchronized EEG patterns. Concurrent, low-intensity 100 Hz stimulation of the basal amygdala permitted EEG activation to tail pressure to occur, and strongly enhanced olfactory-induced cortical activation. These results indicate that excitation of the basal amygdala potentiates frontal cortical responsiveness to aversive sensory events. This may provide a mechanism to facilitate cortical excitability and processing by amygdaloid neuronal activity.

Reinforcement of Early Long-Term Potentiation (Early-LTP) in Dentate Gyrus by Stimulation of the Basolateral Amygdala: Heterosynaptic Induction Mechanisms of Late-LTP

The basolateral amygdala (BLA) can influence distinct learning and memory formation. Hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation, can be modulated by stimulation of the BLA in its induction and early maintenance. However, it is not known how the late maintenance of LTP beyond its initial phases might be affected. Behavioral stimuli have been shown to result in a reinforcement of a transient early-LTP into a lasting potentiation. Here we show that BLA stimulation mimics the behavioral effects on early-LTP in freely moving rats when the BLA is activated within a time window of 30 min before or after tetanization of the perforant path. The reinforcement of LTP was blocked by inhibitors of muscarinergic and beta-adrenergic but not dopaminergic receptors and was dependent on translation. Through these heterosynaptic associative interactions, hippocampal sensory information can be stabilized by amygdaloidal influences.

Monoamines and seizures: microdialysis findings in locus ceruleus and amygdala before and during amygdala kindling

We used microdialysis to determine extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) before and during a 1-day amygdala kindling paradigm. Subjects were young cats (<1 year old; n=8; 6 female, 2 male). Consecutive 5-min samples (2 μl/min infusion rate) were obtained from left amygdala and ipsilateral locus ceruleus complex (LC) under 3 experimental conditions lasting 1-h each ( n=12 samples per cat per condition): (1) just before amygdala stimulation (baseline), (2) during focal afterdischarge (AD) and (3) during generalized AD. ADs were elicited by electrical stimulation applied to establish thresholds immediately before dialysate collection as well as during each sample collected in focal vs. generalized AD conditions. Sample concentrations were time-adjusted to correspond with sleep vs. waking state and/or focal vs. generalized ADs. Seizure activity was indexed by AD threshold (mA) and duration (s) as well as number and duration of specific clinically evident (behavioral) seizure manifestations. Main results were: (1) Lower baseline concentrations (fmoles per sample) of NE, DA and 5-HT correlated with subsequent increases in duration of focal and generalized AD as well as number of behavioral seizure correlates. (2) When compared to baseline levels, NE, DA and 5-HT concentrations significantly increased only in amygdala during focal AD and in both amygdala and LC during generalized AD. (3) NE and 5-HT concentrations were higher than DA at both collection sites and were selectively associated with increased wakefulness throughout the study.

Raphe region mediates changes in cutaneous vascular tone elicited by stimulation of amygdala and hypothalamus in rabbits

Raphe pallidus/parapyramidal neurons control cutaneous vasoconstriction induced by noxious stimuli. To determine whether they mediate forebrain-induced cutaneous vasoconstriction, we assessed changes in ear pinna blood flow elicited by electrical stimulation of amygdala and hypothalamus before and after injection of muscimol into the raphe/parapyramidal region. We compared ear flow with simultaneously recorded mesenteric flow. Experiments were performed in rabbits anesthetized with urethane (1.25–1.5 g/kg), paralysed and mechanically ventilated. Amygdala stimulation reduced skin conductance from 0.32±0.06 to 0.10±0.02 cm/s per mm Hg ( P<0.05, n=9), without effect on mesenteric conductance. Hypothalamic stimulation caused vasoconstriction in both cutaneous and mesenteric beds (conductances fell from 0.27±0.05 to 0.05±0.02 cm/s per mm Hg and from 0.27±0.06 to 0.14±0.04 cm/s per mm Hg ( P<0.05, n=9), respectively). Muscimol microinjection (5 nmol in 100 nl) to raphe/parapyramidal region eliminated amygdala- and hypothalamus-induced skin vasoconstriction (pre-stimulus conductance 0.42±0.13 and 0.41±0.11 cm/s per mm Hg, post-stimulus 0.41±0.12 and 0.39±0.10 cm/s per mm Hg, respectively), but not hypothalamically-induced mesenteric vasoconstriction (pre-stimulus 0.29±0.06, post-stimulus 0.16±0.03 cm/s per mm Hg, P<0.05, n=8). The latter was strongly attenuated by bilateral injection of muscimol to the rostral ventrolateral medulla. Data suggest that descending hypothalamo–spinal and amygdala–spinal pathways constricting the cutaneous vascular bed relay in the raphe/parapyramidal area. A relay in the rostral ventrolateral medulla contributes substantially to mesenteric vasoconstriction elicited from the hypothalamus.

Modulation of Hippocampal Long-Term Potentiation by the Amygdala: A Synaptic Mechanism Linking Emotion and Memory

Why are emotionally arousing experiences well-remembered? Since the amygdala and hippocampus play pivotal roles in emotion and memory, respectively, the interaction between these brain regions may underlie the formation of enhanced memory for emotionally arousing events. Behavioral experiments using animals have demonstrated that lesions of the amygdaloid nuclei or infusions of drugs into the amygdaloid nuclei impair or enhance hippocampal-dependent learning. In addition, we have obtained direct evidence that neural inputs from the amygdala modulate synaptic plasticity in the hippocampus, through electrophysiological experiments using anesthetized rats. Electrical stimulation of the basolateral amygdala evoked synaptic potentials in the dentate gyrus of the hippocampus, indicating that there is a neural connection from the amygdala to the hippocampus. Lesion of the basolateral or basomedial, but not central, amygdala resulted in attenuation of long-term potentiation (LTP) at the perforant path-dentate gyrus granule cell synapses. High-frequency stimulation of the basolateral or basomedial amygdala alone did not induce LTP in the dentate gyrus, but facilitated the induction of LTP when applied at the same time as tetanic stimulation of the perforant path. The activity-dependent facilitation of hippocampal LTP by the basomedial and basolateral amygdala may be a synaptic mechanism underlying memory enhancement associated with emotions.

Lamotrigine treatment during amygdala-kindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy.

Lamotrigine (LTG) is an anticonvulsant that is currently in use for the treatment of various seizure disorders and that shows promise in the treatment of affective illness. LTG is also effective in the suppression of amygdala-kindled seizures. Because many drugs show a differential efficacy profile as a function of the phase of kindling evolution, we evaluated LTG for its potential antiepileptogenic effects on the development of amygdala-kindled seizures. In two separate studies, LTG (5 or 15 mg/kg versus vehicle) was administered before each daily amygdala stimulation (biphasic square wave pulses, 100 pulse pairs per second for a total of 0.5 second, 1-millisecond pulse width) at an intensity of 50 microA over the AD threshold. Seizure development was assessed, as well as the effect of this pretreatment on subsequent efficacy of LTG on completed kindled seizures. LTG at 5 mg/kg failed to block seizure development. At 15 mg/kg, LTG paradoxically enhanced seizure development and produced running fits in four of the nine animals tested. Animals previously treated with either dose of LTG during kindling development showed a diminished response to the anticonvulsant effects of LTG on fully kindled seizures compared with the vehicle-treated controls. Although LTG possesses potent anticonvulsant effects on completed amygdala-kindled seizures, it is either without effect (5 mg/kg) or facilitates (15 mg/kg) the initial phase of kindling development. In addition, exposure to LTG during kindled seizure development leads to a reduced subsequent response to the drug in fully kindled animals. These observations parallel those with carbamazepine and suggest that different stages of kindling (epileptogenesis versus fully manifest seizures) may have different underlying neural mechanisms that require distinct pharmacotherapies.

The Involvement of Apoptotic Neural Damages in a Patient with Intractable Temporal Lobe Epilepsy and in a Kindling Model

Purpose: Human temporal lobe cpilepsy is frequently related to loss of hippocampal neurons, called hippocampal sclerosis. It is still controversial whether neuronal cell death is directly involved in the pathogenesis or epilepsy or whether it is a secondary phenomenon following recurrent seizures. The present study aims to clarify the contribution of neuronal apoptotic changes to the basic pathophysiology of epilepsy. We investigated apoptotic neural damage in the hippocampi of both a patient with intractable temporal lobe epilepsy and an amygdaloidkindling epilepsy model. Methods: The patient was a 30‐year old male who had a 15‐year history of drug‐resistant complex partial seizures. His seizure frequency increased to 5–10 seizures per week. Scalp EEG revealed right temporal‐dominant spikes, and spike and slow wave complexes. Frequent epileptic spike discharges from the right mid‐hippocampal region were detected by eicctrocorticography (ECoG) before temporal lobectomy. Samples of right hippocampal tissue were obtained during surgery. We cxamined apoptotic brain damage by i n situ terminal deoxynuclcotidyltraiisferase‐mediated dUTP nick‐end labeling of fragmented DNA (TUNEL) in the. hippocampal formation removed at surgery. We also examined the involvement of apoptotic brain damage in the kindling model of epilepsy. Sprague‐Dawley rats were kindled by a daily electrical stimulation in the left hasolateral amygdala with a SOHz biphasic square wave at an intensity just above the afterdischarge threshold for 2 seconds. The analysis was performed in the resected right hippocampus of the patient and in partially‐kindled (PK) and lully‐kindled (FK; 20 consecutive generalized convulsions) rats, 24 hours after the last seizure. After fixation i n 10% neutral‐buffered formalin, brain tissue was embedded i n paraffin. Coronal sections werc ording to ordinary TUNEL method. Immunoreactivity of Bax and the expression level of bax mRNA by in situ hybridination were alsn examined. Results: Apoptotic brain damage was observed in the spike‐detected and non spike‐detected areas of the patient's hippocampus. More DNA‐fragmented nuclei were seen i n non spike‐detected areas than in the spike‐detected areas. Only a few DNA‐fragmented nuclei were detected in the spike‐detected area. Compared with the spike‐detected area, an increased expression of Bax protein and bax mRNA levels was observed in non spike‐detected areas. In the kindling model, an increased number of TUNEL positive cells were secn in the CA3 and CA4 from the PK group rats. Only a few DNA‐fragmented nuclei were seen in the hippocampus from the FK group rats. The relative increase in expression levels of Bax protein and bax mRNA was observed in the CA3 and CA4 in both kindled groups. Conclusions: I1 we hypothesize that results from both human temporal lobe epilepsy and kindling models arise from a common basis in the pathophysiology of epilepsy, apoptotic cell death in hippocampus is induced not only by recurrent seizures, but also by factors rclated to the aquiaition process of epileptogenesis. The present results might be associated with the hippocainpal synaptic reorganization. However, clarification of this relationship requires further study. Our detection of changes in apoptosis‐related genes such as Bax and neuronal apoptotic cell death suggests their contribution to the pathogenesis of epilepsy.

Cocaine and Kindling Alter the Sensitivity of Group II and III Metabotropic Glutamate Receptors in the Central Amygdala

G-protein-coupled metabotropic glutamate receptors (mGluRs) are being implicated in various forms of neuroplasticity and CNS disorders. This study examined whether the sensitivities of mGluR agonists are modulated in a distinct fashion in different models of synaptic plasticity, specifically, kindling and chronic cocaine treatment. The influence of kindling and chronic cocaine exposure in vivo was examined in vitro on the modulation of synaptic transmission by group II and III metabotropic glutamate receptors using whole cell voltage-clamp recordings of central amygdala (CeA) neurons. Synaptic transmission was evoked by electrical stimulation of the basolateral amygdala (BLA) and ventral amygdaloid pathway (VAP) afferents in brain slices from control rats and from rats treated with cocaine or exposed to three to five stage-five kindled seizures. This study shows that after chemical stimulation with chronic cocaine exposure or after electrical stimulation with kindling the receptor sensitivities for mGluR agonists are altered in opposite ways. In slices from control rats, group II agonists, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1) and (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), depressed neurotransmission more potently at the BLA-CeA than at the VAP-CeA synapse while group III agonist, L(+)-2-amino-4-phosphonobutyrate (LAP4), depressed neurotransmission more potently at the VAP-CeA synapse than at the BLA-CeA. These agonist actions were not seen (were absent) in amygdala neurons from chronic cocaine-treated animals. In contrast, after kindling, concentration response relationships for LCCG1 and LAP4 were shifted to the left, suggesting that sensitivity to these agonists is increased. Except at high concentrations, LCCG1, LY354740, and LAP4 neither induced membrane currents nor changed current-voltage relationships. Loss of mGluR inhibition with chronic cocaine treatment may contribute to counter-adaptive changes including anxiety and depression in cocaine withdrawal. Drugs that restore the inhibitory effects of group II and III mGluRs may be novel tools in the treatment of cocaine dependence. The enhanced sensitivity to group II and III mGluR agonists in kindling is similar to that recorded at the lateral to BLA synapse in the amygdala where they reduce epileptiform bursting. These findings suggest that drugs modifying mGluRs may prove useful in the treatment of cocaine withdrawal or epilepsy.

Antinociception produced by mu opioid receptor activation in the amygdala is partly dependent on activation of mu opioid and neurotensin receptors in the ventral periaqueductal gray

Exposure to stressful or fear-inducing environmental stimuli activates descending antinociceptive systems resulting in a decreased pain response to peripheral noxious stimuli. Stimulating mu opioid receptors in the basolateral nucleus of the amygdala (BLA) in anesthetized rats produces antinociception that is similar to environmentally induced antinociception in awake rats. Recent evidence suggests that both forms of antinociception are mediated via projections from the amygdala to the ventral periaqueductal gray (PAG). In the present study, we examined the types of neurochemicals released in the ventral PAG that may be important in the expression of antinociception produced by amygdala stimulation in anesthetized rats. Microinjection of a mu opioid receptor agonist into the BLA resulted in a time dependent increase in tail flick latency that was attenuated by preadministration of a mu opioid receptor or a neurotensin receptor antagonist into the ventral PAG. Microinjection of a delta 2 opioid receptor antagonist or an NMDA receptor antagonist into the ventral PAG was ineffective. These findings suggest that amygdala stimulation produces antinociception that is mediated in part by opioid and neurotensin release within the ventral PAG.

The effect of amygdala stimulation to the neural propagation from the perirhinal cortex to the entorhinal/hippocampal neurocircuit

The effect of amygdala stimulation to the neural propagation from the perirhinal cortex to the entorhinal/hippocampal neurocircuit

Biphasic Modulation of Hippocampal Plasticity by Behavioral Stress and Basolateral Amygdala Stimulation in the Rat

Explicit memory may depend on the hippocampus, whereas the amygdala may be part of an emotional memory system. Priming stimulation of the basolateral group of the amygdala (BLA) resulted in an enhanced long-term potentiation (LTP) in the dentate gyrus (DG) to perforant path (PP) stimulation 30, 90, 150, and 180 min after high-frequency stimulation (HFS). Exposure of rats to a behavioral stress is reported to inhibit DG LTP. Because the amygdala is thought to mediate emotional responses, we examined the apparent discrepancy between the effects of behavioral stress induced 1 hr before HFS to the PP and of amygdala priming on hippocampal plasticity by stimulating the BLA 1 hr before HFS to the PP. The two delayed protocols inhibited the expression of LTP to PP stimulation, whereas priming the BLA immediately before HFS to the PP enhanced DG LTP. Moreover, exposure to the behavioral stress blocked the enhancing effects of BLA priming on LTP. We propose that the activation of the BLA (either by behavioral stress or by direct electrical stimulation) has a biphasic effect on hippocampal plasticity: an immediate excitatory effect and a longer-lasting inhibitory effect.

Effect of pirenzepine, a muscarinic M 1 receptor antagonist, on amygdala kindling in rat

Kindling, an animal model of complex partial seizures with secondary generalization, is performed by daily application of low-intensity electrical brain stimulation. The purpose of this study was to investigate the role of muscarinic M 1 receptors on amygdala kindling in the rat. Bipolar nichrome stimulation and recording electrodes were stereotaxically implanted into the right and left basolateral amygdala. Extradural recording electrodes were also placed bilaterally in the skull over the cortex. Amygdala stimulation was applied twice daily at the current intensity of afterdischarge threshold. Seizure intensity was graded by using Racine’s standard five-stage scale. In the first group of experiments, saline or pirenzepine (10, 25, 50 and 100 nmol), a muscarinic M 1 receptor antagonist, was injected intracerebroventricularly 1 h before the electrical stimulation. In the second group of experiments, rats were kindled to full stage 5 seizures. After a recovery period, 50 nmol of pirenzepine was administered intracerebroventricularly to kindled animals. In the first group of experiments, none of the animals pretreated with the doses of 50 and 100 nmol of pirenzepine reached a stage 5 seizure. Pirenzepine significantly retarded kindling seizure development and increased the total number of stimulations required to reach the first stage 5 seizure. Afterdischarge duration was also reduced in the pirenzepine 10 nmol group as compared with that in the saline-pretreated group. In the second group, seizure stage and afterdischarge duration were not affected by pirenzepine in fully-kindled animals. The findings of this study suggest that muscarinic M 1 receptors may have a critical role in the development of kindling epileptic activity, but not in already kindled seizures.

Anxiety in a transgenic mouse model of cortical-limbic neuro-potentiated compulsive behavior.

Anxiety and amygdalar stimulation may induce or exacerbate compulsions triggered by cortical-limbic hyperactivity, as in human obsessive-compulsive disorder (OCD). We previously created transgenic mice that exhibit OCD-like biting, movement and behavioral perseverance abnormalities. These behaviors are caused by expression of a neuro-potentiating cholera toxin (CT) transgene in dopamine D1 receptor-expressing (D1+) neurons within the amygdalar intercalated nucleus (ICN) and within cortical areas that project to orbitofrontal cortex and striatum. Here we tested whether anxiety and increased amygdalar stimulation may play a role in eliciting or exacerbating such behaviors. D1CT mice exhibited increased thigmotaxis (tendency of mice to remain along the perimeter of open areas) in the open field assay, and increased latency to first transit and reduced transit number in the light-dark assay. These studies indicate that the D1CT mice exhibit a significant increase in behavioral indicators of anxiety. Furthermore, yohimbine, a drug that induces both amygdalar stimulation and behavioral indicators of anxiety, exacerbated abnormal leaping in D1CT mice but failed to exacerbate their abnormal behavioral perseverance. These data suggest that chronic potentiation of D1+ neurons in the amygdalar ICN increases anxiety and facilitates particular compulsive behaviors.

Role of zinc released by stimulation in rat amygdala

The movement and role of actively functioning zinc, i.e., vesicular zinc, in the amygdala was studied, based on the data that 65Zn is localized in the limbic system, which may correspond to the regions with high densities of zinc-containing neuron terminals. When release of 65Zn into the extracellular space was examined 2 hr or 25 hr after injection of 65ZnCl2 into the amygdala, 65Zn release was facilitated by stimulation with high K+ 2 hr after injection, but not 25 hr after injection. Even 25 hr after 65Zn injection into the amygdala, approximately 95% of total 65Zn in the brain was detected in the injected area. These results suggest that zinc released into the extracellular space in the amygdala is not readily restored to the presynaptic vesicles. Moreover, to chelate zinc in the extracellular space (and in the synaptic vesicles) in the amygdala, the amygdalae were perfused with 10 μM diethyldithiocarbamate during behavioral tests for odor recognition. The olfactory sensation was temporarily disturbed by the perfusion. These results suggest that vesicular zinc is essential to the function of the amygdala, e.g., olfactory function. J. Neurosci. Res. 57:405–410, 1999. © 1999 Wiley-Liss, Inc.

Evidence that limbic neural plasticity in the right hemisphere mediates partial kindling induced lasting increases in anxiety-like behavior: effects of low frequency stimulation (quenching?) on long term potentiation of amygdala efferents and behavior following kindling

Behavioral and physiological effects of partial kindling of the right ventral hippocampus by perforant path (PP) stimulation were investigated in the cat. Partial kindling produced lasting changes in affect (increased defensive response to rats) and predatory attack (decreased pawing and biting attack). Partial kindling also induced long term potentiation (LTP) of amygdala efferent transmission to ventromedial hypothalamus (VMH) and periaqueductal gray (PAG) in left and right hemispheres. LTP of field population spikes evoked in area CA3 by PP stimulation was also observed. LTP was detected using evoked potential methods. These findings parallel previous studies of left PP-CA3 partial kindling. Analysis of covariance removing effects of LTP from behavioral changes suggests that initiation of increased defensiveness at 2 days after completion of partial kindling depended on LTP of left and right amygdalo–VMH and right amygdalo–PAG transmission. From 6 days after kindling onward, increased defensiveness depended on LTP of right amygdalo–PAG transmission. Depotentiation of amygdala efferent LTP by bilateral low frequency amygdala stimulation (LFS) (900 pulses at 1 Hz, once daily for 7 days) selectively reduced LTP in right amygdala efferents. At the same time, defensive, but not predatory attack behavior, was returned to levels seen prior to partial kindling. Both depotentiation and reduction of defensiveness were transient. Defensiveness increased to post-kindling levels by 76 days after LFS. At the same time, LTP was restored in the right amygdalo–PAG pathway. In contrast LTP in the right amygdalo–VMH pathway remained depotentiated. Effects of LFS were not due to damage, as thresholds to evoke amygdala efferent response were unchanged. These findings suggest that lasting change in affect following partial hippocampal kindling depends on LTP of right amygdala efferent transmission to PAG. The findings parallel studies of non-convulsant pharmacological induction of lasting increases in defensiveness and amygdalo–PAG LTP with FG-7142. The parallel between the present findings and the FG-7142 experiments suggests that lasting changes in defensive response are dependent on LTP of right amygdala efferents to the PAG, however produced. The findings suggest further that the spectrum of behavioral changes produced by partial kindling are dependent on changes in a variety of neural circuits, and that amygdala efferent transmission changes are responsible for changes in defensive behavior, but not predatory attack behavior. Clinical implications are discussed.

Role of zinc released by stimulation in rat amygdala

The movement and role of actively functioning zinc, i.e., vesicular zinc, in the amygdala was studied, based on the data that 65Zn is localized in the limbic system, which may correspond to the regions with high densities of zinc-containing neuron terminals. When release of 65Zn into the extracellular space was examined 2 hr or 25 hr after injection of 65ZnCl2 into the amygdala, 65Zn release was facilitated by stimulation with high K+ 2 hr after injection, but not 25 hr after injection. Even 25 hr after 65Zn injection into the amygdala, approximately 95% of total 65Zn in the brain was detected in the injected area. These results suggest that zinc released into the extracellular space in the amygdala is not readily restored to the presynaptic vesicles. Moreover, to chelate zinc in the extracellular space (and in the synaptic vesicles) in the amygdala, the amygdalae were perfused with 10 microM diethyldithiocarbamate during behavioral tests for odor recognition. The olfactory sensation was temporarily disturbed by the perfusion. These results suggest that vesicular zinc is essential to the function of the amygdala, e.g., olfactory function.