Distinct VIP interneurons in the cingulate cortex encode anxiogenic and social stimuli

ABSTRACTA hallmark of higher-order cortical regions is their functional heterogeneity, but it is not well understood how these areas encode such diverse information. The anterior cingulate cortex (ACC), for example, is important in both emotional regulation and social cognition. Previous work shows activation of the ACC to anxiety-related and social stimuli, but it is unknown how subpopulations or microcircuits within the ACC simultaneously encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to alter the activity of many cells in local cortical microcircuits, but it is unknown whether the activity of VIP cells in the ACC (VIPACC) encodes anxiety-related or social information. Using in vivo calcium imaging and miniscopes in freely behaving mice to monitor VIPACC activity, we identified distinct, non-overlapping subpopulations of VIPACC that preferentially activated to either anxiogenic, anxiolytic, social, or non-social stimuli. We determined that stimulus-selective cells encode the animal’s behavioral states and VIP interneuron clusters may co-activate, improving this encoding. Finally, we used trans-synaptic tracing to show that VIPACC receive widespread inputs from regions implicated in emotional regulation and social cognition. These findings demonstrate not only that the ACC is not homogeneous in its function, but also that there is marked functional heterogeneity even within disinhibitory interneuron populations. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

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Intentional communication and the anterior cingulate cortex

Interaction Studies ◽

10.1075/is.6.2.04ben ◽

2005 ◽

Vol 6 (2) ◽

pp. 201-221 ◽

Cited By ~ 7

Author(s):

Oana Benga

Keyword(s):

Social Cognition ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Neural Structure ◽

Intentional Communication ◽

Attention Skills ◽

Starting Point ◽

Prelinguistic Communication ◽

Critical Structure

This paper presents arguments for considering the anterior cingulate cortex (ACC) as a critical structure in intentional communication. Different facets of intentionality are discussed in relationship to this neural structure. The macrostructural and microstructural characteristics of ACC are proposed to sustain the uniqueness of its architecture, as an overlap region of cognitive, affective and motor components. At the functional level, roles played by this region in communication include social bonding in mammals, control of vocalization in humans, semantic and syntactic processing, and initiation of speech. The involvement of the anterior cingulate cortex in social cognition is suggested where, for infants, joint attention skills are considered both prerequisites of social cognition and prelinguistic communication acts. Since the intentional dimension of gestural communication seems to be connected to a region previously equipped for vocalization, ACC might well be a starting point for linguistic communication.

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Role for NMDA receptors in visceral nociceptive transmission in the anterior cingulate cortex of viscerally hypersensitive rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00452.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. G918-G927 ◽

Cited By ~ 25

Author(s):

Xiaoyin Wu ◽

Jun Gao ◽

Jin Yan ◽

Jing Fan ◽

Chung Owyang ◽

...

Keyword(s):

Nmda Receptors ◽

Receptor Antagonist ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Neuronal Firing ◽

Anterior Cingulate ◽

High Dose ◽

Glutamatergic Transmission ◽

Reverse Microdialysis

We have identified colorectal distension (CRD)-responsive neurons in the anterior cingulate cortex (ACC) and demonstrated that persistence of a heightened visceral afferent nociceptive input to the ACC induces ACC sensitization. In the present study, we confirmed that rostral ACC neurons of sensitized rats [induced by chicken egg albumin (EA)] exhibit enhanced spike responses to CRD. Simultaneous in vivo recording and reverse microdialysis of single ACC neurons showed that a low dose of glutamate (50 μM) did not change basal ACC neuronal firing in normal rats but increased ACC neuronal firing in EA rats from 18 ± 2 to 32 ± 3.8 impulses/10 s. A high dose of glutamate (500 μM) produced 1.95-fold and a 4.27-fold increases of ACC neuronal firing in sham-treated rats and in EA rats, respectively, suggesting enhanced glutamatergic transmission in the ACC neurons of EA rats. Reverse microdialysis of the 3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainite receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 μM) reduced basal and abolished CRD-induced ACC neuronal firing in normal rats. In contrast, microdialysis of N-methyl-d-aspartate (NMDA) receptor antagonist AP5 had no effect on ACC neuronal firing in normal rats. However, AP5 produced 86% inhibition of ACC neuronal firing evoked by 50 mmHg CRD in the EA rats. In conclusion, ACC nociceptive transmissions are mediated by glutamate AMPA receptors in the control rats. ACC responses to CRD are enhanced in viscerally hypersensitive rats. The enhancement of excitatory glutamatergic transmission in the ACC appears to mediate this response. Furthermore, NMDA receptors mediate ACC synaptic responses after the induction of visceral hypersensitivity.

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In vivo evidence for early neurodevelopmental anomaly of the anterior cingulate cortex in bipolar disorder

Acta Psychiatrica Scandinavica ◽

10.1111/j.1600-0447.2007.01069.x ◽

2007 ◽

Vol 116 (6) ◽

pp. 467-472 ◽

Cited By ~ 28

Author(s):

A. Fornito ◽

G. S. Malhi ◽

J. Lagopoulos ◽

B. Ivanovski ◽

S. J. Wood ◽

...

Keyword(s):

Bipolar Disorder ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate

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Metabolite activity in the anterior cingulate cortex during a painful stimulus using functional MRS

Scientific Reports ◽

10.1038/s41598-020-76263-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

J. Archibald ◽

E. L. MacMillan ◽

C. Graf ◽

P. Kozlowski ◽

C. Laule ◽

...

Keyword(s):

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Noxious Stimulation ◽

Resonance Spectroscopy ◽

Large Effect Size ◽

Brain Responses ◽

Pain Outcomes ◽

Healthy Participants

Abstract To understand neurochemical brain responses to pain, proton magnetic resonance spectroscopy (1H-MRS) is used in humans in vivo to examine various metabolites. Recent MRS investigations have adopted a functional approach, where acquisitions of MRS are performed over time to track task-related changes. Previous studies suggest glutamate is of primary interest, as it may play a role during cortical processing of noxious stimuli. The objective of this study was to examine the metabolic effect (i.e., glutamate) in the anterior cingulate cortex during noxious stimulation using fMRS. The analysis addressed changes in glutamate and glutamate + glutamine (Glx) associated with the onset of pain, and the degree by which fluctuations in metabolites corresponded with continuous pain outcomes. Results suggest healthy participants undergoing tonic noxious stimulation demonstrated increased concentrations of glutamate and Glx at the onset of pain. Subsequent reports of pain were not accompanied by corresponding changes in glutamate of Glx concentrations. An exploratory analysis on sex revealed large effect size changes in glutamate at pain onset in female participants, compared with medium-sized effects in male participants. We propose a role for glutamate in the ACC related to the detection of a noxious stimulus.

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Cerebral Metabolism during Propofol Anesthesia in Humans Studied with Positron Emission Tomography

Anesthesiology ◽

10.1097/00000542-199502000-00010 ◽

1995 ◽

Vol 82 (2) ◽

pp. 393-403 ◽

Cited By ~ 214

Author(s):

Michael T. Alkire ◽

Richard J. Haier ◽

Steven J. Barker ◽

Nitin K. Shah ◽

Joseph C. Wu ◽

...

Keyword(s):

Positron Emission Tomography ◽

Animal Studies ◽

Cerebral Metabolism ◽

Anterior Cingulate ◽

Emission Tomography ◽

Whole Brain ◽

Metabolic Pattern ◽

Positron Emission ◽

Cortical Regions

Background Although the effects of propofol on cerebral metabolism have been studied in animals, these effects have yet to be directly examined in humans. Consequently, we used positron emission tomography (PET) to demonstrate in vivo the regional cerebral metabolic changes that occur in humans during propofol anesthesia. Methods Six volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism, and the other assessed metabolism during anesthesia with a propofol infusion titrated to the point of unresponsiveness (mean rate +/- SD = 7.8 +/- 1.5 mg.kg-1.h-1). Scans were obtained using the 18fluorodeoxyglucose technique. Results Awake whole-brain glucose metabolic rates (GMR) averaged 29 +/- 8 mumoles.100 g-1.min-1 (mean +/- SD). Anesthetized whole-brain GMR averaged 13 +/- 4 mumoles.100 g-1.min-1 (paired t test, P < or = 0.007). GMR decreased in all measured areas during anesthesia. However, the decrease in GMR was not uniform. Cortical metabolism was depressed 58%, whereas subcortical metabolism was depressed 48% (P < or = 0.001). Marked differences within cortical regions also occurred. In the medial and subcortical regions, the largest percent decreases occurred in the left anterior cingulate and the inferior colliculus. Conclusion Propofol produced a global metabolic depression on the human central nervous system. The metabolic pattern evident during anesthesia was reproducible and differed from that seen in the awake condition. These findings are consistent with those from previous animal studies and suggest PET may be useful for investigating the mechanisms of anesthesia in humans.

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Deficits in Selective Attention Following Bilateral Anterior Cingulotomy

Journal of Cognitive Neuroscience ◽

10.1162/jocn.1991.3.3.231 ◽

1991 ◽

Vol 3 (3) ◽

pp. 231-241 ◽

Cited By ~ 77

Author(s):

Kevin W. Janer ◽

José V. Pardo

Keyword(s):

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Neuropsychological Measures ◽

Positron Emission ◽

Cognitive Operations ◽

Before And After ◽

Attentional System ◽

Cortical Regions ◽

High Level

Positron emission tomographic (PET) studies of normal humans undergoing specific cognitive activation paradigms have identified a region of the anterior cingulate cortex as a component of an anterior, midline attentional system involved in high-level processing selection. However, deficits in attention have not been demonstrated in patients following bilateral anterior cingulotomy, a procedure that results in lesions of adjacent anterior cingulate cortex. Task paradigms used in PET studies that recruit the anterior cingulate cortex were applied to normal, control subjects and to a patient before and after cingulotomy to provide highly sensitive and functionally targeted reaction time measures of attentional performance. In contrast to unchanged performance in several neuropsychological measures, this patient demonstrated specific deficits in attention during the subacute postoperative period, which resolved spontaneously several months after surgery. Such impairment is consistent with the evolving view of the anterior cingulate's involvement in high-level processing selection. These data show the feasibility of using information from PET activation studies of normals in the design of novel chronometric tasks useful for probing abnormalities in specific cognitive operations associated with discrete cortical regions.

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Anterior cingulate cortex and ventral hippocampal inputs to the basolateral amygdala selectively control generalized fear

10.1101/620237 ◽

2019 ◽

Author(s):

Samantha Ortiz ◽

Maeson S. Latsko ◽

Julia L. Fouty ◽

Sohini Dutta ◽

Jordan M. Adkins ◽

...

Keyword(s):

Anxiety Disorders ◽

Anterior Cingulate Cortex ◽

Basolateral Amygdala ◽

Cingulate Cortex ◽

Underlying Mechanism ◽

Anterior Cingulate ◽

Time Dependent ◽

Common Symptom ◽

Independent Manner ◽

Cortical Regions

AbstractNearly one third of Americans have been afflicted with an anxiety disorder. A common symptom of anxiety disorders is the over generalization of fear across a broad range of contextual cues. We previously found that the anterior cingulate cortex and ventral hippocampus (vHPC) regulate generalized fear. Here, we investigate the functional projections from the ACC and vHPC to the amygdala and their role in governing generalized fear in a preclinical rodent model. A chemogenetic approach (DREADDs) was used to inhibit glutamatergic projections from the ACC or vHPC that terminate within the basolateral amygdala (BLA) at recent (1 day) or remote (28 days) time points after contextually fear conditioning male mice. Inactivating ACC or vHPC projections to the BLA significantly reduced generalized fear to a novel, nonthreatening context but had no effect on fear to the training context. Further, our data indicate that the ACC-BLA circuit supports generalization in a time-independent manner. We also identified for the first time a strictly time-dependent role of the vHPC-BLA circuit in supporting remote generalized contextual fear. Dysfunctional signaling to the amygdala from the ACC or the hippocampus could underlie over-generalized fear responses that are associated with anxiety disorders. Our findings demonstrate that the ACC and vHPC regulate fear expressed in novel, nonthreatening environments via projections to the BLA but do so as a result of training intensity or time, respectively.Significance StatementAnxiety disorders are characterized by a common symptom that promotes overgeneralization of fear in non-threatening environments. Dysregulation of the amygdala, anterior cingulate cortex (ACC), or hippocampus has been hypothesized to contribute to increased fear associated with anxiety disorders. Our findings show that the ACC and HPC projections to the basolateral amygdala regulate generalized fear in non-threatening, environments. However, descending ACC projections control fear generalization independent of time, whereas HPC projections play a strictly time-dependent role in regulating generalized fear. Thus, dysfunctional ACC/HPC signaling to the BLA may be a predominant underlying mechanism of non-specific fear associated with anxiety disorders. Our data have important implications for predictions made by theories about aging memories and interactions between the hippocampus and cortical regions.

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Individual pain sensitivity is associated with resting-state cortical activities in healthy individuals but not in patients with migraine: a magnetoencephalography study

The Journal of Headache and Pain ◽

10.1186/s10194-020-01200-8 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Fu-Jung Hsiao ◽

Wei-Ta Chen ◽

Hung-Yu Liu ◽

Yen-Feng Wang ◽

Shih-Pin Chen ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Pain Sensitivity ◽

Large Population ◽

Cingulate Cortex ◽

Gamma Oscillation ◽

Anterior Cingulate ◽

Healthy Individuals ◽

Clinical Pain ◽

Cortical Regions

Abstract Background Pain sensitivity may determine the risk, severity, prognosis, and efficacy of treatment of clinical pain. Magnetic resonance imaging studies have linked thermal pain sensitivity to changes in brain structure. However, the neural correlates of mechanical pain sensitivity remain to be clarified through investigation of direct neural activities on the resting-state cortical oscillation and synchrony. Methods We recorded the resting-state magnetoencephalographic (MEG) activities of 27 healthy individuals and 30 patients with episodic migraine (EM) and analyzed the source-based oscillatory powers and functional connectivity at 2 to 59 Hz in pain-related cortical regions, which are the bilateral anterior cingulate cortex (ACC), medial orbitofrontal (MOF) cortex, lateral orbitofrontal (LOF) cortex, insula cortex, primary somatosensory cortex (SI), primary motor cortex (MI), and posterior cingulate cortex (PCC). The mechanical punctate pain threshold (MPPT) was obtained at the supraorbital area (the first branch of the trigeminal nerve dermatome, V1) and the forearm (the first thoracic nerve dermatome, T1) and further correlated with MEG measures. Results The MPPT is inversely correlated with the resting-state relative powers of gamma oscillation in healthy individuals (all corrected P < 0.05). Specifically, inverse correlation was noted between the MPPT at V1 and gamma powers in the bilateral insula (r = − 0.592 [left] and − 0.529 [right]), PCC (r = − 0.619 and − 0.541) and MI (r = − 0.497 and − 0.549) and between the MPPT at T1 and powers in the left PCC (r = − 0.561) and bilateral MI (r = − 0.509 and − 0.520). Furthermore, resting-state functional connectivity at the delta to beta bands, especially between frontal (MOF, ACC, LOF, and MI), parietal (PCC), and sensorimotor (bilateral SI and MI) regions, showed a positive correlation with the MPPT at V1 and T1 (all corrected P < 0.05). By contrast, in patients with EM, the MPPT was not associated with resting-state cortical activities. Conclusions Pain sensitivity in healthy individuals is associated with the resting-state gamma oscillation and functional connectivity in pain-related cortical regions. Further studies must be conducted in a large population to confirm whether resting-state cortical activities can be an objective measurement of pain sensitivity in individuals without clinical pain.

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