Stimulation Of Basolateral Amygdala Research Articles

Prelimbic and infralimbic responsivity to amygdala input is modified by gonadal hormones in parallel to low anxiety-like behavior in ovariectomized rats

Gonadal hormones may influence sexual activity by reducing anxiety. The basolateral amygdala (BLA) and prelimbic (PL) and infralimbic (IL) cortical regions comprise a loop that is related to fear, anxiety, and social behavior. In female ovariectomized rats, actions of estradiol, progesterone, and sequential estradiol and progesterone administration were explored in the open field test (OFT) and plus maze test (PMT) to evaluate signs of anxiety-like behavior. The three hormonal treatments reduced indicators of anxiety in the PMT but did not influence behavior in the OFT. In the same behaviorally tested rats under urethane anesthesia, single-unit extracellular recordings were obtained from the PL and IL during electrical stimulation of the BLA. The analysis of 250 ms peristimulus histograms showed that BLA stimulation produced two kinds of response. A small group of neurons increased their firing rate after BLA stimulation. Most neurons exhibited a reduction of spiking. Neurons that increased their firing rate after BLA stimulation did not show any difference with the hormonal treatments. In neurons that were inhibited by BLA stimulation, estradiol reduced the neuronal firing rate in the PL and IL, and progesterone alone and the sequential administration of estradiol followed by progesterone administration 24 h later (priming) increased the firing rate during the 240 ms before BLA stimulation. Analyses of responsivity of the PL and IL during electrical stimulation of the BLA indicated that estradiol, progesterone, and estradiol followed by progesterone administration 24 h later (priming) reduced inhibitory actions of the BLA on the PL but not IL. In the BLA-IL connection, progesterone exacerbated the inhibitory response. These findings indicate that anxiolytic actions of estradiol, progesterone, and estradiol followed by progesterone administration 24 h later (priming) correspond to lower BLA-PL responsivity. Actions of progesterone on BLA-IL responsivity appear to contribute to sexual activity by interacting with other forebrain structures that are also related to sexual receptivity.

Distinct contributions of ventral CA1/amygdala co-activation to the induction and maintenance of synaptic plasticity.

The amygdala is known to modulate hippocampal synaptic plasticity. One role could be an immediate effect of basolateral amygdala (BLA) in priming synaptic plasticity in the hippocampus. Another role could be through associative synaptic co-operation and competition that triggers events involved in the maintenance of synaptic potentiation. We present evidence that the timing and activity level of BLA stimulation are important factors for the induction and maintenance of long-term potentiation (LTP) in ventral hippocampal area CA1. A 100Hz BLA co-stimulation facilitated the induction of LTP, whereas 200Hz co-stimulation attenuated induction. A 100Hz BLA co-stimulation also caused enhanced persistence, sufficient to prevent synaptic competition. This maintenance effect is likely through translational mechanisms, as mRNA expression of primary response genes was unaffected, whereas protein level of plasticity-related products was increased. Further understanding of the neural mechanisms of amygdala modulation on hippocampus could provide insights into the mechanisms of emotional disorders.

Basolateral amygdala stimulation plus water maze training restore dentate gyrus LTP and improve spatial learning and memory

Synaptic plasticity is a key mechanism of neural plasticity involved in learning and memory. A reduced or impaired synaptic plasticity could lead to a deficient learning and memory. On the other hand, besides reducing hipocampal dependent learning and memory, fimbria-fornix lesion affects LTP. However, we have consistently shown that stimulation of the basolateral amygdala (BLA) 15 min after water maze training is able to improve spatial learning and memory in fimbria fornix lesioned rats while also inducing changes in the expression of plasticity-related genes expression in memory associated brain regions like the hippocampus and prefrontal cortex. In this study we test that hypothesis: whether BLA stimulation 15 min after water maze training can improve LTP in the hippocampus of fimbria-fornix lesioned rats. To address this question, we trained fimbria-fornix lesioned rats in water maze for four consecutive days, and the BLA was bilaterally stimulated 15 min after each training session.Our data show that trained fimbria-fornix lesioned rats develop a partially improved LTP in dentated gyrus compared with the non-trained fimbria-fornix lesioned rats. In contrast, dentated gyrus LTP in trained and BLA stimulated fimbria-fornix lesioned rats improved significantly compared to the trained fimbria-fornix lesioned rats, but was not different from that shown by healthy animals. BLA stimulation in non-trained FF lesioned rats did not improve LTP; instead produces a transient synaptic depression. Restoration of the ability to develop LTP by the combination of training and BLA stimulation would be one of the mechanisms involved in ameliorating memory deficits in lesioned animals.

2-Heptanone reduces inhibitory control of the amygdala over the prelimbic region in rats

Basolateral amygdala (BLA) nuclei and their reciprocal connections with prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex (mPFC) are involved in the regulation of fear. 2-Heptanone is released in urine in stressed rats, and the olfactory detection of this odor produces immediate avoidance and alarm reactions and modifies neuronal activity in limbic connections in non-stressed rats. If 2-heptanone acts as a danger signal, then long-lasting actions would be expected. The aim of the present study was to investigate whether the forced inhalation of 2-heptanone modifies the response capacity of the BLA-mPFC circuit in the long term (48 h). Single-unit extracellular recordings were obtained from the PL and IL during electrical stimulation of the BLA (square-wave pulses; 1 ms, 20 µA, 0.3 Hz, 110 stimuli over a total duration of 360 s) in three groups of Wistar rats: control group (no sensory stimulation), unpredictable auditory stimulation group, and 2-heptanone stimulation group. A brief-latency (1 ms), short-duration (5 ms) paucisynaptic response followed BLA stimulation and was unaffected by any sensorial stimulation. The paucisynaptic response was followed by a mostly inhibitory and long-lasting (>750 ms) afterdischarge in the control and auditory stimulation groups. In the 2-heptanone group, the inhibitory afterdischarge shifted to an excitatory afterdischarge after ∼250 ms in the PL and after ∼500 ms in the IL. Importantly, the rats that were included in this study were born in local housing facilities. Thus, these animals were never in contact with predators and instead in contact with only conspecifics. These results indicate that the forced inhalation of 2-heptanone is able to modify BLA-mPFC responsivity in the long term. 2-Heptanone decreases inhibitory control of the amygdala over mPFC activity. Disinhibition of the mPFC may lead to the adaptive expression of defensive behaviors, even in animals that are not in the presence of predators.

Input-dependent synaptic suppression by pregabalin in the central amygdala in male mice with inflammatory pain

Pregabalin (PGB) is a synthetic amino acid compound most widely prescribed for chronic peripheral and central neuropathic pain. PGB is a ligand for the α2δ1 subunit of voltage-dependent calcium channels, and its binding reduces neurotransmitter release and thus inhibits synaptic transmission. The central nucleus of the amygdala (CeA) is a kernel site for the enhanced nociception-emotion link in chronic pain. The nociceptive information is conveyed to the CeA via the following two pathways: 1) the pathway arising from the basolateral amygdala (BLA), which carries nociceptive information mediated by the thalamocortical system, and 2) that arising from the external part of the pontine lateral parabrachial nucleus (LPB), that forms the final route of the spino-parabrachio-amygdaloid pathway that conveys nociceptive information directly from the superficial layer of the spinal dorsal horn. We compared the effects of PGB on the excitatory postsynaptic currents of neurons in the right CeA in response to electrical stimulation of BLA and LPB pathways using the whole-cell patch-clamp technique. Inflammatory pain was induced by intraplantar injection of formalin solution at the left hind paw.At eight hours post-formalin, PGB reduced EPSCs amplitude of the BLA-to-CeA synaptic transmission, accompanied by a significant increase in the PPR, suggesting a decreased release probability from the presynaptic terminals. In addition, these effects of PGB were only seen in inflammatory conditions. PGB did not affect the synaptic transmission at the LPB-to-CeA pathway, even in formalin-treated mice. These results suggest PGB improves not simply the aberrantly enhanced nociception but also various pain-associated cognitive and affective consequences in patients with chronic nociplastic pain.

Stress impacts corticoamygdalar connectivity in an age-dependent manner.

Stress is a socio-environmental risk factor for the development of psychiatric disorders, with the age of exposure potentially determining the outcome. Several brain regions mediate stress responsivity, with a prominent role of the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) and their reciprocal inhibitory connectivity. Here we investigated the impact of stress exposure during adolescence and adulthood on the activity of putative pyramidal neurons in the BLA and corticoamygdalar plasticity using in vivo electrophysiology. 155 male Sprague-Dawley rats were subjected to a combination of footshock/restraint stress in either adolescence (postnatal day 31-40) or adulthood (postnatal day 65-74). Both adolescent and adult stress increased the number of spontaneously active putative BLA pyramidal neurons 1-2 weeks, but not 5-6 weeks post stress. High-frequency stimulation (HFS) of BLA and mPFC depressed evoked spike probability in the mPFC and BLA, respectively, in adult but not adolescent rats. In contrast, an adult-like BLA HFS-induced decrease in spike probability of mPFC neurons was found 1-2 weeks post-adolescent stress. Changes in mPFC and BLA neuron discharge were found 1-2 weeks post-adult stress after BLA and mPFC HFS, respectively. All these changes were transient since they were not found 5-6 weeks post adolescent or adult stress. Our findings indicate that stress during adolescence may accelerate the development of BLA-PFC plasticity, probably due to BLA hyperactivity, which can also disrupt the reciprocal communication of BLA-mPFC after adult stress. Therefore, precocious BLA-mPFC connectivity alterations may represent an early adaptive stress response that ultimately may contribute to vulnerability to adult psychiatric disorders.

Low-threshold spiking interneurons perform feedback inhibition in the lateral amygdala

Amygdala plays crucial roles in emotional learning. The lateral amygdala (LA) is the input station of the amygdala, where learning related plasticity occurs. The LA is cortical like in nature in terms of its cellular make up, composed of a majority of principal cells and a minority of interneurons with distinct subtypes defined by morphology, intrinsic electrophysiological properties and neurochemical expression profile. The specific functions served by LA interneuron subtypes remain elusive. This study aimed to elucidate the interneuron subtype mediating feedback inhibition. Electrophysiological evidence involving antidromic activation of recurrent LA circuitry via basolateral amygdala stimulation and paired recordings implicate low-threshold spiking interneurons in feedback inhibition. Recordings in somatostatin-cre animals crossed with tdtomato mice have revealed remarkable similarities between a subset of SOM+ interneurons and LTS interneurons. This study concludes that LTS interneurons, most of which are putatively SOM+, mediate feedback inhibition in the LA. Parallels with cortical areas and potential implications for information processing and plasticity are discussed.

Amygdala rapid kindling impairs breathing in response to chemoreflex activation

Temporal lobe epilepsy is often accompanied by behavioral, electroencephalographic and autonomic abnormalities. Amygdala kindling has been used as an experimental model to study epileptogenesis. Although amygdala kindling has been extensively investigated in the context of its clinical relevance to the epilepsies, potential associated respiratory alterations are not well known. Here, our main objective was to better investigate the mechanisms involved in respiratory physiology impairment in the amygdala rapid kindling (ARK) model of epileptogenesis. Male Wistar rats with electrodes implanted into the amygdaloid complex were used. After recovery from surgery, the rats were subjected to electrical stimulation of basolateral amygdala for 2 consecutive days (10 stimuli/day). The ventilatory parameters were evaluated by whole body plethysmography. Thereafter, animals were also exposed to hypercapnia (7% CO2) for 3 h to evaluate fos protein expression in several nuclei involved in respiratory control. We observed a significant reduction in ventilation during the ictal phase elicited by ARK. We also found that 10 days after ARK, baseline ventilation as well as the hypercapnia ventilatory response (7% CO2) were reduced compared to control rats. The number of fos-immunoreactive neurons in the retrotrapezoid nucleus, raphe magnus and nucleus of the solitary tract were also reduced after ARK. Our results showed that ARK was able to impair breathing function, demonstrating a strong coupling between amygdala and the respiratory neurons in the brainstem, with potential impact in respiratory failures, frequently fatal, during or after epileptic seizures in chronic animal models and in patients.

Commonalities and differences in extracellular levels of hippocampal acetylcholine and amino acid neurotransmitters during status epilepticus and subsequent epileptogenesis in two rat models of temporal lobe epilepsy

Chemically or electrically induced status epilepticus (SE) in rodents is a commonly used method for induction of epilepsy. Structural and functional changes in the hippocampus play a pivotal role in epileptogenesis induced by SE. Although cholinergic mechanisms have long been thought to play an important role in the onset and propagation of epileptic seizures, not much is known about the potential role of acetylcholine (ACh) in ictogenesis and epileptogenesis in SE models of temporal lobe epilepsy. Here we used in vivo microdialysis to determine extracellular levels of ACh and, for comparison, several amino acid transmitters in the ventral hippocampus during SE, epileptogenesis, and the chronic epileptic state in two rat models of SE-induced epilepsy. SE was either induced by lithium-pilocarpine or by sustained electrical stimulation of the basolateral amygdala (BLA). ACh increased during SE in both models. Pretreatment with the muscarinic receptor antagonist scopolamine before BLA stimulation reduced SE severity and duration. In contrast to ACh, no consistent changes in amino acid levels were found during SE in the two models. During epileptogenesis and the chronic epileptic state, the only commonalities found in both models were a decrease in ACh in epileptic rats during the chronic epileptic state and a decrease in aspartate during epileptogenesis. The data demonstrate complex, model-dependent alterations in extracellular levels of ACh and amino acid neurotransmitters and only few commonalities. Thus, data originating from only one model of post-SE epilepsy should not be generalized but may have a limited translational value for understanding ictogenesis or epileptogenesis.

Bilateral amygdala stimulation reduces avoidance behavior in a predator scent posttraumatic stress disorder model.

OBJECTIVE The predator scent model of posttraumatic stress disorder (PTSD) produces prolonged abnormal anxiety and avoidance-like behaviors. Increased basolateral amygdala activity has been shown to correlate with severity of PTSD symptoms in human studies. Modulation of this increased amygdala activity by deep brain stimulation led to improved symptoms in prior studies that used a foot shock model of inducing PTSD. The predator scent model is a different technique that induces long-lasting avoidance behavioral responses by exposing the animal to an inescapable scent of one of its predators. The authors hypothesize that high-frequency stimulation of the bilateral basolateral amygdala will decrease avoidance and anxiety-like behaviors in a predator scent rodent model of PTSD. METHODS Rodents underwent cat urine exposure in a place preference protocol. Avoidance in the place preference paradigm and anxiety-like behavior in the elevated plus maze were measured before and after high-frequency stimulation. RESULTS Predator scent exposure resulted in long-term significant avoidance behavior in rodents. Bilateral stimulation significantly decreased avoidance behavior in rodents compared to no stimulation following predator scent exposure. There were no significant differences in anxiety behaviors on the elevated plus maze between stimulated and unstimulated cohorts. CONCLUSIONS Bilateral stimulation of the basolateral amygdala leads to decreased avoidance behavior compared to controls in a predator scent model of PTSD.

Amygdala stimulation promotes recovery of behavioral performance in a spatial memory task and increases GAP-43 and MAP-2 in the hippocampus and prefrontal cortex of male rats

The relationships between affective and cognitive processes are an important issue of present neuroscience. The amygdala, the hippocampus and the prefrontal cortex appear as main players in these mechanisms. We have shown that post-training electrical stimulation of the basolateral amygdala (BLA) speeds the acquisition of a motor skill, and produces a recovery in behavioral performance related to spatial memory in fimbria-fornix (FF) lesioned animals. BLA electrical stimulation rises bdnf RNA expression, BDNF protein levels, and arc RNA expression in the hippocampus. In the present paper we have measured the levels of one presynaptic protein (GAP-43) and one postsynaptic protein (MAP-2) both involved in synaptogenesis to assess whether structural neuroplastic mechanisms are involved in the memory enhancing effects of BLA stimulation. A single train of BLA stimulation produced in healthy animals an increase in the levels of GAP-43 and MAP-2 that lasted days in the hippocampus and the prefrontal cortex. In FF-lesioned rats, daily post-training stimulation of the BLA ameliorates the memory deficit of the animals and induces an increase in the level of both proteins. These results support the hypothesis that the effects of amygdala stimulation on memory recovery are sustained by an enhanced formation of new synapses.

Methylene Blue Exerts Anticonvulsant and Neuroprotective Effects on Self-Sustaining Status Epilepticus (SSSE) Induced by Prolonged Basolateral Amygdala Stimulation in Wistar Rats.

BackgroundThis study was designed to investigate the potential anticonvulsant and neuroprotective effects of methylene blue (MB) on self-sustaining status epilepticus (SSSE) induced by prolonged basolateral amygdala stimulation (BLA) in Wistar rats.Material/MethodsThe rats were randomly divided into 4 groups: (1) the Control group (rats without any treatment); (2) the Sham group (rats received electrode implantation but without electrical stimulation); (3) the SSSE group (rats received electrode implantation and additional electrical stimulation); and (4) the SSSE+MB group (rats received 1 mg/kg MB intraperitoneal injection 5 min after SSSE). SSSE models were established by prolonged BLA stimulation. The severities of SSSE were assessed by the number of separate seizures and the accumulated time of seizures. The variations of malondialdehyde/glutathione (MDA/GSH) were assessed 24 h after the establishment of SSSE. Nissl staining was performed to detect the surviving neurons in hippocampal CA1 and CA3 regions, and Western blotting assays were used to detect Caspase-3 (CASP3), B cell lymphoma 2 (BCL2), and BCL2-associated X protein (BAX).ResultsCompared with the SSSE group, treatment with MB (1) markedly reduced the number and accumulated time of seizure activities; (2) significantly attenuated the increase of MDA and the decrease of GSH hippocampal levels; (3) markedly improved the cell morphology and alleviated the neuronal loss in hippocampal CA1 and CA3 regions; (4) significantly attenuated the increase of CASP3 and BAX and the decrease of BCL2 hippocampal levels.ConclusionsMB has a protective effect in the SSSE model and may be useful as an adjuvant for preventing or treating epilepsy in humans.

Kindling epileptogenesis and panic-like behavior: Their bidirectional connection and contribution to epilepsy-associated depression

Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy–PLB comorbidity.

Low-frequency electrical stimulation enhances the effectiveness of phenobarbital on GABAergic currents in hippocampal slices of kindled rats

Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100μM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital.

MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice

This study investigated the effects of a single administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridinyl-4-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), a negative allosteric modulator (NAM) of metabotropic glutamate receptor 7 (mGluR7), on pain and on affective and cognitive behavior in neuropathic mice. The activity of pyramidal neurons in the prelimbic cortex (PLC), which respond to stimulation of the basolateral amygdala (BLA) with either excitation or inhibition, was also investigated. The spared nerve injury (SNI) of the sciatic nerve induced, 14 days after surgery, thermal hyperalgesia and mechanical allodynia, reduced open-arm choice in the elevated plus-maze, increased time of immobility in the tail suspension, and increased digging and burying in the marble burying test. Cognitive performance was also significantly compromised in the SNI mice. Spared nerve injury induced phenotypic changes on pyramidal neurons of the PLC; excitatory responses increased, whereas inhibitory responses decreased after BLA stimulation. mGluR7 expression, mainly associated with vesicular glutamate transporter, increased in the hippocampus and decreased in the BLA, PLC, and dorsal raphe in SNI mice. MMPIP increased thermal and mechanical thresholds and open-arm choice. It reduced the immobility in the tail suspension test and the number of marbles buried and of digging events in the marble burying test. MMPIP also improved cognitive performance and restored the balance between excitatory and inhibitory responses of PLC neurons in SNI mice. 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one, XAP044, another selective mGluR7 NAM, reproduced the effects of MMPIP on thermal hyperalgesia, mechanical allodynia, tail suspension, and marble burying test. Altogether, these findings show that mGluR7 NAMs reduce pain responses and affective/cognitive impairments in neuropathic pain conditions.

Optogenetic excitation of central amygdala amplifies and narrows incentive motivation to pursue one reward above another.

Choosing one reward above another is important for achieving adaptive life goals. Yet hijacked into excessive intensity in disorders such as addiction, single-minded pursuit becomes maladaptive. Here, we report that optogenetic channelrhodopsin stimulation of neurons in central nucleus of amygdala (CeA), paired with earning a particular sucrose reward in rats, amplified and narrowed incentive motivation to that single reward target. Therefore, CeA rats chose and intensely pursued only the laser-paired sucrose reward while ignoring an equally good sucrose alternative. In contrast, reward-paired stimulation of basolateral amygdala did not hijack choice. In a separate measure of incentive motivation, CeA stimulation also increased the progressive ratio breakpoint or level of effort exerted to obtain sucrose reward. However, CeA stimulation by itself failed to support behavioral self-stimulation in the absence of any paired external food reward, suggesting that CeA photo-excitation specifically transformed the value of its external reward (rather than adding an internal reinforcement state). Nor did CeA stimulation by itself induce any aversive state that motivated escape. Finally, CeA stimulation also failed to enhance 'liking' reactions elicited by sucrose taste and did not simply increase the general motivation to eat. This pattern suggests that CeA photo-excitation specifically enhances and narrows incentive motivation to pursue an associated external reward at the expense of another comparable reward.

Combined sub-threshold dosages of phenobarbital and low-frequency stimulation effectively reduce seizures in amygdala-kindled rats

Low-frequency stimulation (LFS) is a potential therapy utilized in patients who do not achieve satisfactory control of seizures with pharmacological treatments. Here, we investigated the interaction between anticonvulsant effects of LFS and phenobarbital (a commonly used medicine) on amygdala-kindled seizures in rats. Animals were kindled by electrical stimulation of basolateral amygdala in a rapid manner (12 stimulations/day). Fully kindled animals randomly received one of the three treatment choices: phenobarbital (1, 2, 3, 4 and 8 mg/kg; i.p.; 30 min before kindling stimulation), LFS (one or 4 packages contained 100 or 200 monophasic square wave pulses, 0.1-ms pulse duration at 1 Hz, immediately before kindling stimulation) or a combination of both (phenobarbital at 3 mg/kg and LFS). Phenobarbital alone at the doses of 1, 2 and 3 mg/kg had no significant effect on the main seizure parameters. LFS application always produced anticonvulsant effects unless applied with the pattern of one package of 100 pulses, which is considered as non-effective. All the seizure parameters were significantly reduced when phenobarbital (3 mg/kg) was administered prior to the application of the non-effective pattern of LFS. Phenobarbital (3 mg/kg) also increased the anticonvulsant actions of the effective LFS pattern. Our results provide an evidence of a positive cumulative anticonvulsant effect of LFS and phenobarbital, suggesting a potential combination therapy at sub-threshold dosages of phenobarbital and LFS to achieve a satisfactory clinical effect.

Prolonged depth electrode implantation in the limbic system increases the severity of status epilepticus in rats

Chronically implanted intracranial depth electrodes are widely used for studying electroencephalographic activities in deep cerebral locations and for electrical stimulation of such locations. We have previously reported that prolonged implantation of an electrode in the basolateral amygdala (BLA) of rats facilitates subsequent kindling from this site, indicating a pro-kindling or pro-epileptogenic effect. To further characterize this phenomenon, we analyzed data from experiments in which we induced a self-sustaining status epilepticus (SSSE) by BLA stimulation following different periods of post-surgical delay. In a total of 183 Sprague-Dawley rats, three groups with different periods of postsurgical delay to onset of electrical stimulation were compared: group 1 (16 days on average), group 2 (28 days) and group 3 (48 days). Three types of SSSE were observed after BLA stimulation: type 1 (nonconvulsive), type 2 (nonconvulsive occasionally interrupted by generalized convulsive activity), and type 3 (generalized convulsive). While groups 1 and 2 did not differ in the frequency of these SSSE types, the group with the longest interval between electrode implantation and stimulation (group 3) showed significantly more severe SSSE than the two other groups. The data indicate that intracranial electrode implantation may increase the sensitivity of the implanted area to seizure induction, extending previous findings in the kindling model. Potential mechanisms of these findings include the functional consequences of local microhemorrhages and blood-brain barrier destruction.

Persistent Cocaine-Induced Reversal Learning Deficits Are Associated with Altered Limbic Cortico-Striatal Local Field Potential Synchronization

Repeated exposure to cocaine is known to produce persistent deficits in behavioral flexibility. Evidence suggests that these deficits are mediated in part by a circuit involving the medial prefrontal and orbitofrontal cortices (PFC and OFC), nucleus accumbens (NAC), and basolateral amygdala (BLA). To assess the effects of cocaine on this circuit, we treated rats with cocaine daily for 14 d, followed by 4 weeks of abstinence. Animals were then tested on a cross-maze-based reversal learning and set-shifting task, after which they were anesthetized to allow for recording of spontaneous local field potential (LFP) activity simultaneously from all four regions, in addition to activity evoked from acute BLA stimulation. Cocaine-treated (COC) animals showed specific deficits in reversal learning; furthermore, spontaneous LFP oscillation power was reduced and BLA-induced oscillation power was increased in all regions compared with saline-treated (SAL) rats. Theta-burst stimulation of BLA potentiated BLA-evoked responses in all regions and cocaine challenge reduced spontaneous oscillation power and evoked response amplitude, with no COC/SAL group differences. Notably, cocaine challenge produced differential changes in coherence between OFC-BLA, BLA-NAC, and OFC-NAC in COC and SAL groups. These data indicate that repeated exposure to cocaine can produce changes in oscillatory LFP synchronization along limbic cortico-striatal circuits that persist long into abstinence. Furthermore, the regional specificity of these changes strongly correlates with the observed behavioral deficits. Aberrant synchronization within and between regions and consequent dysregulation of the neurocircuitry involved in executive control may contribute to the long-lasting maladaptive decision making seen in cocaine abusers.

Emergence of GABAergic-dependent regulation of input-specific plasticity in the adult rat prefrontal cortex during adolescence

The prefrontal cortex (PFC) receives multiple cortical and subcortical afferents that regulate higher order cognitive functions, many of which emerge late in adolescence. However, it remains unclear how these afferents influence PFC processing, especially in light of the protracted, late adolescent maturation of prefrontal GABAergic function. Here we investigated the role of PFC GABAergic transmission in regulating plasticity elicited from the ventral hippocampus and basolateral amygdala, and how such modulation undergoes functional changes during adolescence in rats. In vivo local field potential recordings, combined with prefrontal microinfusion of the GABA-A receptor antagonist picrotoxin, were employed to study the impact of ventral hippocampal and basolateral amygdala high-frequency stimulation on PFC plasticity. Ventral hippocampal-induced PFC plasticity begins to appear only by postnatal days (P) 45-55 with a transient suppression of the evoked response. A switch from transient to long-lasting depression (LTD) of the PFC response emerges after P55 and throughout adulthood (P65-120). Recordings conducted in the presence of picrotoxin revealed that PFC GABAergic transmission is critical for the expression of LTD. In contrast, basolateral amygdala stimulation resulted in PFC long-term potentiation, a form of plasticity that is already enabled by P30 and is insensitive to picrotoxin. The development of ventral hippocampal-dependent PFC LTD is contingent upon the recruitment of local prefrontal GABAergic transmission during adolescence whereas plasticity elicited from the basolateral amygdala is not. Thus, different mechanisms contribute to the refinement of prefrontal plasticity during adolescence as inputs from these two regions are critical for shaping PFC functions.