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The posterior intralaminar thalamus innervates L-ITCcs. a, Micrograph showing the PHA-L injection site in the posterior paralaminar thalamic nuclei for rat no. 7. Neuronal nuclear antigen (NeuN) immunoreactivity reveals neuronal cell bodies. b, Line drawing of a rat brain coronal section (Paxinos and Watson, 2007) showing an overview of the extent of PHA-Llabeled cells in three animals, selected from a larger series of injections (n 7). In these cases, the injection site was mostly confined to the target, i.e., posterior intralaminar thalamus, comprising PIL, PoT, and Po. Each injection is illustrated with a different green shading pattern. Little variability in the pattern of axonal labeling was observed among these three injections. c, PHA-L anterograde tracing of projections from the posterior intralaminar thalamus (green) to mGlu1 L-ITCc (red). d, e, Thalamic axons made frequent appositions with mGlu1 L-ITCc dendrites. f, Synapse between a PHA-L-filled axon terminal (DAB staining) and a mGlu1 (immunometal particles; arrows) L-ITCc dendrite. Scale bars: a, 1 mm; c, 500 m; d, e, 10 m; f, 500 nm. APT, Anterior pretectal nucleus; BA, basal nucleus; CeA, central nucleus; d, dendrite; MGn, medial geniculate nucleus; ml, medial lemniscus; PIL, posterior intralaminar thalamic nucleus; Po, posterior thalamic nuclear group; PP, peripeduncular nucleus; SNR, substantia nigra, reticular part.
Source publication
Various GABAergic neuron types of the amygdala cooperate to control principal cell firing during fear-related and other behaviors, and understanding their specialized roles is important. Among GABAergic neurons, the so-called intercalated cells (ITCcs) are critically involved in the expression and extinction of fear memory. Tightly clustered small-...
Contexts in source publication
Context 1
... intralaminar thalamic nuclei (PIN) are thought to carry nociceptive information to the amygdala and participate in syn- aptic plasticity underlying fear memory formation ( Linke et al., 2000). We postulated that L-ITCcs receive synaptic inputs from this thalamic region, accounting for L-ITCc responses to noxious stimuli. Therefore, we next tested the innervation of dorsomedial mGlu1 L-ITCcs following the injection of the anterograde tracer PHA-L in the PIN. As the injection site was correctly placed and restricted to the PIN in 3 of 7 rats (Fig. 8a,b), tract tracing was further analyzed only in sections from these animals. Intense axonal labeling could be observed in the lateral amygdala and AStria (Fig. 8c), as previously described ( Linke et al., 2000). Moreover, using immunofluorescence double-labeling, we found that thalamic axons frequently made close appositions (i.e., putative synapses) with mGlu1 dendrites of L-ITCcs (Fig. 8d,e). Electron microscopic analysis of a subset of these axons confirmed that PHA-L-filled axon terminals of intralami- nar thalamic neurons formed asymmetric synaptic contacts with mGlu1 profiles in the ITC regions (Fig. 8f ). Thus, noxious stimulus-driven excitation of L-ITCcs with the soma located close to the intermediate capsule might result from direct tha- lamic relay, which is consistent with the short latency responses of L-ITCcs to noxious ...
Context 2
... intralaminar thalamic nuclei (PIN) are thought to carry nociceptive information to the amygdala and participate in syn- aptic plasticity underlying fear memory formation ( Linke et al., 2000). We postulated that L-ITCcs receive synaptic inputs from this thalamic region, accounting for L-ITCc responses to noxious stimuli. Therefore, we next tested the innervation of dorsomedial mGlu1 L-ITCcs following the injection of the anterograde tracer PHA-L in the PIN. As the injection site was correctly placed and restricted to the PIN in 3 of 7 rats (Fig. 8a,b), tract tracing was further analyzed only in sections from these animals. Intense axonal labeling could be observed in the lateral amygdala and AStria (Fig. 8c), as previously described ( Linke et al., 2000). Moreover, using immunofluorescence double-labeling, we found that thalamic axons frequently made close appositions (i.e., putative synapses) with mGlu1 dendrites of L-ITCcs (Fig. 8d,e). Electron microscopic analysis of a subset of these axons confirmed that PHA-L-filled axon terminals of intralami- nar thalamic neurons formed asymmetric synaptic contacts with mGlu1 profiles in the ITC regions (Fig. 8f ). Thus, noxious stimulus-driven excitation of L-ITCcs with the soma located close to the intermediate capsule might result from direct tha- lamic relay, which is consistent with the short latency responses of L-ITCcs to noxious ...
Context 3
... intralaminar thalamic nuclei (PIN) are thought to carry nociceptive information to the amygdala and participate in syn- aptic plasticity underlying fear memory formation ( Linke et al., 2000). We postulated that L-ITCcs receive synaptic inputs from this thalamic region, accounting for L-ITCc responses to noxious stimuli. Therefore, we next tested the innervation of dorsomedial mGlu1 L-ITCcs following the injection of the anterograde tracer PHA-L in the PIN. As the injection site was correctly placed and restricted to the PIN in 3 of 7 rats (Fig. 8a,b), tract tracing was further analyzed only in sections from these animals. Intense axonal labeling could be observed in the lateral amygdala and AStria (Fig. 8c), as previously described ( Linke et al., 2000). Moreover, using immunofluorescence double-labeling, we found that thalamic axons frequently made close appositions (i.e., putative synapses) with mGlu1 dendrites of L-ITCcs (Fig. 8d,e). Electron microscopic analysis of a subset of these axons confirmed that PHA-L-filled axon terminals of intralami- nar thalamic neurons formed asymmetric synaptic contacts with mGlu1 profiles in the ITC regions (Fig. 8f ). Thus, noxious stimulus-driven excitation of L-ITCcs with the soma located close to the intermediate capsule might result from direct tha- lamic relay, which is consistent with the short latency responses of L-ITCcs to noxious ...
Context 4
... intralaminar thalamic nuclei (PIN) are thought to carry nociceptive information to the amygdala and participate in syn- aptic plasticity underlying fear memory formation ( Linke et al., 2000). We postulated that L-ITCcs receive synaptic inputs from this thalamic region, accounting for L-ITCc responses to noxious stimuli. Therefore, we next tested the innervation of dorsomedial mGlu1 L-ITCcs following the injection of the anterograde tracer PHA-L in the PIN. As the injection site was correctly placed and restricted to the PIN in 3 of 7 rats (Fig. 8a,b), tract tracing was further analyzed only in sections from these animals. Intense axonal labeling could be observed in the lateral amygdala and AStria (Fig. 8c), as previously described ( Linke et al., 2000). Moreover, using immunofluorescence double-labeling, we found that thalamic axons frequently made close appositions (i.e., putative synapses) with mGlu1 dendrites of L-ITCcs (Fig. 8d,e). Electron microscopic analysis of a subset of these axons confirmed that PHA-L-filled axon terminals of intralami- nar thalamic neurons formed asymmetric synaptic contacts with mGlu1 profiles in the ITC regions (Fig. 8f ). Thus, noxious stimulus-driven excitation of L-ITCcs with the soma located close to the intermediate capsule might result from direct tha- lamic relay, which is consistent with the short latency responses of L-ITCcs to noxious ...
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Loss of inhibition is suggested to cause pathological pain symptoms. Indeed, some human case reports suggest that lesions including the thalamic reticular nucleus (TRN) which provides major inhibitory inputs to other thalamic nuclei, may induce thalamic pain, a type of neuropathic pain. In support, recent studies demonstrated that activation of GAB...
Citations
... It is worth noting that long-range GABAergic neurons are important circuit elements in many brain areas, such as the spiny projection neurons in the striatum, the Purkinje neurons in the cerebellum, and somatostatin-immunoreactive neurons in the amygdala which project to the entorhinal cortex (McDonald & Zaric, 2015) and to the basal forebrain (McDonald et al., 2012). In addition, Bienvenu et al. (2015) have demonstrated that large intercalated neurons of the amygdala project to distant brain areas, such as the perirhinal, entorhinal and endopiriform cortices. ...
Differentiating between auditory signals of various emotional significance plays a crucial role in an individual's ability to thrive and excel in social interactions and in survival. Multiple approaches, including anatomical studies, electrophysiological investigations, imaging techniques, optogenetics and chemogenetics, have confirmed that the auditory cortex (AC) impacts fear‐related behaviours driven by auditory stimuli by conveying auditory information to the lateral amygdala (LA) through long‐range excitatory glutamatergic and GABAergic connections. In addition, the LA provides glutamatergic projections to the AC which are important to fear memory expression and are modified by associative fear learning. Here we test the hypothesis that the LA also sends long‐range direct inhibitory inputs to the cortex. To address this fundamental question, we used anatomical and electrophysiological approaches, allowing us to directly assess the nature of GABAergic inputs from the LA to the AC in the mouse. Our findings elucidate the existence of a long‐range inhibitory pathway from the LA to the AC (LAC) via parvalbumin‐expressing (LAC‐Parv) and somatostatin‐expressing (LAC‐SOM) neurons. This research identifies distinct electrophysiological properties for genetically defined long‐range GABAergic neurons involved in the communication between the LA and the cortex (LAC‐Parv inhibitory projections → AC neurons; LAC‐Som inhibitory projections → AC neurons) within the lateral amygdala cortical network. image
Key points
The mouse auditory cortex receives inputs from the lateral amygdala.
Retrograde viral tracing techniques allowed us to identify two previously undescribed lateral amygdala to auditory cortex (LAC) GABAergic projecting neurons.
Extensive electrophysiological, morphological and anatomical characterization of LAC neurons is provided here, demonstrating key differences in the three populations.
This study paves the way for a better understanding of the growing complexity of the cortico‐amygdala‐cortico circuit.
... The IL inhibits amygdala activation through its projections to GABAergic neurons [38][39][40]. Depressed IL activity reduces inhibition of the amygdala, which contains nociceptive neurons [41]. In addition, the IL also acts on the ventrolateral periaqueductal gray, which plays a crucial role in the descending control of pain [42]. ...
The prelimbic cortex (PL) is actively engaged in pain modulation. The infralimbic cortex (IL) has been reported to regulate the PL. However, how this regulation affects pain remains unclear. In the present study, we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli, but a temporary hypo-function of the IL by in vivo electrophysiological recording in rats with peripheral inflammation. Manipulation of the PL or IL had opposite effects on thermal hyperalgesia. Furthermore, the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL. Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia, whereas its inhibition exacerbated chronic pain. Overall, our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain: hypo-function of the IL leads to hyperactivity of the PL, which regulates thermal hyperalgesia, and thus contributes to the chronicity of pain.
... However, long-range GABAergic projections exist from PV neurons in the cortex to subcortical regions of the brain. In the hippocampus, CA3 and CA1 receive PV neuron projections from the entorhinal cortex (Melzer et al., 2012;Basu et al., 2016;Melzer et al., 2017) and medial septum (Freund and Antal, 1988); and in the amygdala, many of the intercalated cells are PV, projecting to the perirhinal, entorhinal, and piriform cortex (Bienvenu et al., 2015). PV neurons in sensorymotor cortical regions project to the striatum, including the somatosensory cortex (Jinno and Kosaka, 2004), auditory cortex (Rock et al., 2016;Bertero et al., 2020), and primary motor cortex (M1) (Melzer et al., 2017). ...
Background
The commissural inhibitory system between the bilateral medial vestibular nucleus (MVN) plays a key role in vestibular compensation. Calcium-binding protein parvalbumin (PV) is expressed in MVN GABAergic neurons. Whether these neurons are involved in vestibular compensation is still unknown.
Methods
After unilateral labyrinthectomy (UL), we measured the activity of MVN PV neurons by in vivo calcium imaging, and observed the projection of MVN PV neurons by retrograde neural tracing. After regulating PV neurons’ activity by chemogenetic technique, the effects on vestibular compensation were evaluated by behavior analysis.
Results
We found PV expression and the activity of PV neurons in contralateral but not ipsilateral MVN increased 6 h following UL. ErbB4 is required to maintain GABA release for PV neurons, conditional knockout ErbB4 from PV neurons promoted vestibular compensation. Further investigation showed that vestibular compensation could be promoted by chemogenetic inhibition of contralateral MVN or activation of ipsilateral MVN PV neurons. Additional neural tracing study revealed that considerable MVN PV neurons were projecting to the opposite side of MVN, and that activating the ipsilateral MVN PV neurons projecting to contralateral MVN can promote vestibular compensation.
Conclusion
Contralateral MVN PV neuron activation after UL is detrimental to vestibular compensation, and rebalancing bilateral MVN PV neuron activity can promote vestibular compensation, via commissural inhibition from the ipsilateral MVN PV neurons. Our findings provide a new understanding of vestibular compensation at the neural circuitry level and a novel potential therapeutic target for vestibular disorders.
... In contrast to excitatory principal neurons, GABAergic interneurons have thin, spiny dendrites with axons that are usually restricted to the BLA (Kemppainen and Pitknen, 2000). A small proportion of BLA GABAergic interneurons of unknown function have remote projections to regions including the basal forebrain or internal olfactory cortex (Kemppainen and Pitknen, 2000;Bienvenu et al., 2015). Although GABAergic interneurons occupy a relatively small fraction of the whole BLA, GABAergic neurons still play a crucial role in fear extinction. ...
Fear refers to an adaptive response in the face of danger, and the formed fear memory acts as a warning when the individual faces a dangerous situation again, which is of great significance to the survival of humans and animals. Excessive fear response caused by abnormal fear memory can lead to neuropsychiatric disorders. Fear memory has been studied for a long time, which is of a certain guiding effect on the treatment of fear-related disorders. With continuous technological innovations, the study of fear has gradually shifted from the level of brain regions to deeper neural (micro) circuits between brain regions and even within single brain regions, as well as molecular mechanisms. This article briefly outlines the basic knowledge of fear memory and reviews the neurobiological mechanisms of fear extinction and relapse, which aims to provide new insights for future basic research on fear emotions and new ideas for treating trauma and fear-related disorders.
... As previously described, ITCs expressing opioid receptors broadly contribute to this network's oscillatory patterns by firing discretely from hippocampal CA1 theta and gamma oscillations or cortical activity, accounting for ITCs not orchestrating the network oscillation between various brain regions. Interestingly, spike durations recorded from GABAergic neurons and ITCs are comparable, meaning these cells closely coordinate the network activity [268]. ...
The functional interplay between the corticolimbic GABAergic and opioidergic systems plays a crucial role in regulating the reward system and cognitive aspects of motivational behaviors leading to the development of addictive behaviors and disorders. This review provides a summary of the shared mechanisms of GABAergic and opioidergic transmission, which modulate the activity of dopaminergic neurons located in the ventral tegmental area (VTA), the central hub of the reward mechanisms. This review comprehensively covers the neuroanatomical and neurobiological aspects of corticolimbic inhibitory neurons that express opioid receptors, which act as modulators of corticolimbic GABAergic transmission. The presence of opioid and GABA receptors on the same neurons allows for the modulation of the activity of dopaminergic neurons in the ventral tegmental area, which plays a key role in the reward mechanisms of the brain. This colocalization of receptors and their immunochemical markers can provide a comprehensive understanding for clinicians and researchers, revealing the neuronal circuits that contribute to the reward system. Moreover, this review highlights the importance of GABAergic transmission-induced neuroplasticity under the modulation of opioid receptors. It discusses their interactive role in reinforcement learning, network oscillation, aversive behaviors, and local feedback or feedforward inhibitions in reward mechanisms. Understanding the shared mechanisms of these systems may lead to the development of new therapeutic approaches for addiction, reward-related disorders, and drug-induced cognitive impairment.
... They proposed that the time-, target domain-and sensory-specific release of GABA cooperates in promoting amygdalo-hippocampal dialogue and emotional memory formation . In the same series of experiments with Bienvenu and Ferraguti, they also discovered a population of large intercalated GABAergic neurons that widely projected in the brain in addition to innervating other GABAergic neurons in the BLA (Bienvenu et al., 2015). Nociceptive stimulation strongly activated these cells via the thalamus. ...
... Nociceptive stimulation strongly activated these cells via the thalamus. They proposed that large intercalated neurons evoked disinhibition of principal neurons in multiple target areas, coordinating their activity and the animal's response (Bienvenu et al., 2015). Marco continued his work of identifying neurons in the amygdala after he moved to Aarhus University. ...
... One of our main shared achievements has been the elucidation of some of the key structural and functional features of the intercalated cell masses of the amygdala (Bienvenu et al., 2015;Busti et al., 2011;Geracitano et al., 2007Geracitano et al., , 2012. Marco's work has been instrumental in defining several types of BLA interneurons and their role in shaping BLA activity in relation to hippocampal oscillations ( Figure 4) and noxious stimuli, two processes critical for forming emotional memories . ...
... Indeed, BLA projections neurons send strong excitatory input to local parvalbumin (PV) interneurons which are intended to be engaged in feedback inhibition (Smith et al., 2000;Unal et al., 2014). Besides, PV and CB-expressing GABAergic neurons received input from intercalated interneurons which appear to be involved in the disinhibition of projection neurons (Bienvenu et al., 2015;Mańko et al., 2011). A disinhibitory mechanism involved vasoactive intestinal peptide (VIP) interneurons which inhibit the other interneurons within the BLA and participate critically in the regulation of fear (Krabbe et al., 2019). ...
Depression is the second leading cause of disability in the world population, for which currently available pharmacological therapies either have poor efficacy or have some adverse effects. Accumulating evidence from clinical and preclinical studies demonstrates that the amygdala is critically implicated in depressive disorders, though the underlying pathogenesis mechanism needs further investigation. In this literature review, we overviewed depression and the key role of Gamma-aminobutyric acid (GABA) and Glutamate neurotransmission in depression. Notably, we discussed a new cholecystokinin-dependent plastic changes mechanism under stress and a possible antidepressant response of cholecystokinin B receptor (CCKBR) antagonist. Moreover, we discussed the fundamental role of the amygdala in depression, to discuss and understand the pathophysiology of depression and the inclusive role of the amygdala in this devastating disorder.
... They proposed that the time-, target domain-and sensory-specific release of GABA cooperates in promoting amygdalo-hippocampal dialogue and emotional memory formation . In the same series of experiments with Bienvenu and Ferraguti, they also discovered a population of large intercalated GABAergic neurons that widely projected in the brain in addition to innervating other GABAergic neurons in the BLA (Bienvenu et al., 2015). Nociceptive stimulation strongly activated these cells via the thalamus. ...
... Nociceptive stimulation strongly activated these cells via the thalamus. They proposed that large intercalated neurons evoked disinhibition of principal neurons in multiple target areas, coordinating their activity and the animal's response (Bienvenu et al., 2015). Marco continued his work of identifying neurons in the amygdala after he moved to Aarhus University. ...
... One of our main shared achievements has been the elucidation of some of the key structural and functional features of the intercalated cell masses of the amygdala (Bienvenu et al., 2015;Busti et al., 2011;Geracitano et al., 2007Geracitano et al., , 2012. Marco's work has been instrumental in defining several types of BLA interneurons and their role in shaping BLA activity in relation to hippocampal oscillations ( Figure 4) and noxious stimuli, two processes critical for forming emotional memories . ...
Marco Capogna PhD, Professor of Neuroscience at Aarhus University Faculty of Health, Department of Biomedicine, Aarhus, Denmark, died from cancer aged 64 on 2nd December 2022.
... Both rodents and primates contain small, medium-sized spiny neurons, and larger aspiny neurons. The majority of ITCs are small to medium spiny neurons with 9-18 mm soma, and a minority (,5%) are large ITCs (.30 mm ovoid soma) with predominately aspiny dendrites (Millhouse, 1986;Bienvenu et al., 2015). In general, the small ITCs have electronically compact, spiny, often bipolar dendrites confined to the cluster and aligned parallel to the axon track surrounding the BLA in which they reside. ...
... Axonal projections and inhibition are not obviously topographically organized in primate; Instead neurochemical identity determines connectivity patterns (Zikopoulos et al., 2016). The rodent large ITCs mainly reside at the periphery of ITC clusters and express GABA A receptor GABA A R1 and metabotropic glutamate receptor mGluR1a (Bienvenu et al., 2015). Large ITCs surrounding the ITC dm are activated in vivo by noxious stimuli and are innervated by the posterior intralaminar nucleus (PIN) of the thalamus (Bienvenu et al., 2015). ...
... The rodent large ITCs mainly reside at the periphery of ITC clusters and express GABA A receptor GABA A R1 and metabotropic glutamate receptor mGluR1a (Bienvenu et al., 2015). Large ITCs surrounding the ITC dm are activated in vivo by noxious stimuli and are innervated by the posterior intralaminar nucleus (PIN) of the thalamus (Bienvenu et al., 2015). They innervate BLA interneurons and also project to distant brain areas, such as the perirhinal, entorhinal, and endopiriform cortex thereby disinhibiting a distributed network (Bienvenu et al., 2015). ...
Generating adaptive behavioral responses to emotionally salient stimuli requires evaluation of complex associations between multiple sensations, the surrounding context, and current internal state. Neural circuits within the amygdala parse this emotional information, undergo synaptic plasticity to reflect learned associations, and evoke appropriate responses through their projections to the brain regions orchestrating these behaviors. Information flow within the amygdala is regulated by the intercalated cells (ITCs), which are densely packed clusters of GABAergic neurons that encircle the basolateral amygdala (BLA) and provide contextually relevant feedforward inhibition of amygdala nuclei, including the central and BLA. Emerging studies have begun to delineate the unique contribution of each ITC cluster and establish ITCs as key loci of plasticity in emotional learning. In this review, we summarize the known connectivity and function of individual ITC clusters and explore how different neuromodulators conveying internal state act via ITC gates to shape emotionally motivated behavior. We propose that the behavioral state-dependent function of ITCs, their unique genetic profile, and rich expression of neuromodulator receptors make them potential therapeutic targets for disorders, such as anxiety, schizophrenia spectrum, and addiction.
... As previously described, ITCs expressing opioid receptors broadly contribute to this network's oscillatory patterns by firing discretely from hippocampal CA1 theta and gamma oscillations or cortical activity, accounting for ITCs not orchestrating the network oscillation between various brain regions. Interestingly, spike durations recorded from GABAergic neurons and ITCs are comparable, meaning these cells closely coordinate the network activity [268]. ...
Tamoxifen-induced cognitive dysfunction may lead to fluoxetine consumption in patients with breast cancer. Since the brain mechanisms are unclear in tamoxifen/fluoxetine therapy, the blockade effect of hippocampal/amygdala/prefrontal cortical NMDA receptors was examined in fluoxetine/tamoxifen-induced memory retrieval. We also assessed the corticolimbic signaling pathways in memory retrieval under the drug treatment in adult male Wistar rats. Using the Western blot technique, the expression levels of the cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and cFos were evaluated in the corticolimbic regions. The results showed that pre-test administration of fluoxetine (3 and 5 mg/kg, i.p.) improved tamoxifen-induced memory impairment in the passive avoidance learning task. Pre-test bilateral microinjection of D-AP5, a selective NMDA receptor antagonist, into the dorsal hippocampal CA1 regions and the central amygdala (CeA), but not the medial prefrontal cortex (mPFC), inhibited the improving effect of fluoxetine on tamoxifen response. It is important to note that the microinjection of D-AP5 into the different sites by itself did not affect memory retrieval. Memory retrieval increased the signaling pathway of pCREB/CREB/BDNF/cFos in the corticolimbic regions. Tamoxifen-induced memory impairment decreased the hippocampal/PFC BDNF level and the amygdala level of pCREB/CREB/cFos. The improving effect of fluoxetine on tamoxifen significantly increased the hippocampal/PFC expression levels of BDNF, the PFC/amygdala expression levels of cFos, and the ratio of pCREB/CREB in all targeted areas. Thus, NMDA receptors’ activity in the different corticolimbic regions mediates fluoxetine/tamoxifen memory retrieval. The corticolimbic synaptic plasticity changes likely accompany the improving effect of fluoxetine on tamoxifen response.
