Fig 2
Photomicrographs of WGA-HRP injection sites in the thalamus and resultant labeling in the insular cortex. A. Injection site in the VPLpc (R302). B. Anterograde and retrograde labeling in the granular insular cortex following the injection shown in A. C. Injection site in the WMpc (R304) and resultant anterograde and retrograde labeling in the dysgranular insular cortex (D). (cf. description of the injection in Case R304 in Cechetto and Saper, '87.) Scale bars: 500 km.
Source publication
The anterograde and retrograde transport of horseradish peroxidase was used to study the anatomical organization of visceral and limbic terminal fields in the insular cortex. Following injections into the ventroposterolateral parvicellular (VPLpc) and ventroposteromedial parvicellular (VPMpc) visceral relay nuclei of the thalamus, dense anterograde...
Contexts in source publication
Context 1
... injections of tracer into the VPLpc ( Fig. 2A), dense anterograde labeling was observed almost exclusively in the middle and caudal portions of the granular insular cortex (Figs. 2B, 3A, see also Fig. 10A). In case R302 ( Fig. 2A), the injection site included the VPLpc with light spread of tracer dorsally into the ventroposterolateral nucleus and ventrally into the dorsolateral ...
Context 2
... injections of tracer into the VPLpc ( Fig. 2A), dense anterograde labeling was observed almost exclusively in the middle and caudal portions of the granular insular cortex (Figs. 2B, 3A, see also Fig. 10A). In case R302 ( Fig. 2A), the injection site included the VPLpc with light spread of tracer dorsally into the ventroposterolateral nucleus and ventrally into the dorsolateral part of the zona incerta, which do not project to the insular cortex (Saper, '82a). Labeled fibers extended laterally from the injection site ...
Context 3
... injections of tracer into the VPLpc ( Fig. 2A), dense anterograde labeling was observed almost exclusively in the middle and caudal portions of the granular insular cortex (Figs. 2B, 3A, see also Fig. 10A). In case R302 ( Fig. 2A), the injection site included the VPLpc with light spread of tracer dorsally into the ventroposterolateral nucleus and ventrally into the dorsolateral part of the zona incerta, which do not project to the insular cortex (Saper, '82a). Labeled fibers extended laterally from the injection site into the internal capsule, traversed the ...
Context 4
... part of the zona incerta, which do not project to the insular cortex (Saper, '82a). Labeled fibers extended laterally from the injection site into the internal capsule, traversed the striatum in a dorsolatera1 direction, entering the external capsule, and terminating in the insular cortex, ipsilaterally. In the granular insular cortex (Figs. 2B, 3A), dense anterograde labeling was observed in layers 111, IV, and VI. Moderate to light anterograde labeling was observed in layers I1 and V. Dense retrograde labeling was located mainly in layer VI and the deep part of layer V. Figure 2C shows a representative injection (R304) into the VF'Mpc. There was some spread of tracer from the ...
Context 5
... 3A), dense anterograde labeling was observed in layers 111, IV, and VI. Moderate to light anterograde labeling was observed in layers I1 and V. Dense retrograde labeling was located mainly in layer VI and the deep part of layer V. Figure 2C shows a representative injection (R304) into the VF'Mpc. There was some spread of tracer from the core of the injection site dorsally and medially into the intralaminar thalamic nuclei, including the parafascicular and centromedial nuclei. ...
Citations
... The aIC is also bidirectionally connected to the amygdala, the hippocampus, and the mPFC [72] and projects to the NAc, conferring the aIC a central role in guiding motivated behavior, as further supported by the absence of correlation in the salinepriming condition. Conversely, the pIC preferentially processes sensory information through inputs from visceral thalamic sensory nuclei and somatosensory cortex [73]. Decreased activity in anterior insular subregions after extinction of priming, but no change in the pIC, coupled with shared positive correlations between saline and cocaine priming, suggests once again interoceptive cocaine effects may be decoupled from their predicted value, thereby attenuating goal-directed cocaine seeking. ...
... In the current study, the FG labeled neurons were distributed selectively within the AId. Prior work investigated anterior and posterior AI regions, which contains AId (Allen et al. 1991;Shi and Cassell 1998). The FG neurons within the AId were concentrated in layer 2-3, with sparse labelling in layer 1 and 5. Projections to CEA from AId layer 2-3 implicates early sensory information processing. ...
It is adaptive to restrict eating under uncertainty, such as during habituation to novel foods and unfamiliar environments. However, sustained restrictive eating can become maladaptive. Currently, the neural substrates of restrictive eating are poorly understood. Using a model of feeding avoidance under novelty, our recent study identified forebrain activation patterns and found evidence that the central nucleus of the amygdala (CEA) is a core integrating node. The current study analyzed the activity of CEA inputs in male and female rats to determine if specific pathways are recruited during feeding under novelty. Recruitment of direct inputs from the paraventricular nucleus of the thalamus (PVT), the infralimbic cortex (ILA), the agranular insular cortex (AI), the hippocampal ventral field CA1, and the bed nucleus of the stria terminals (BST) was assessed with combined retrograde tract tracing and Fos induction analysis. The study found that during consumption of a novel food in a novel environment, larger number of neurons within the PVTp and the CA1 that send monosynaptic inputs to the CEA were recruited compared to controls that consumed familiar food in a familiar environment. The ILA, AI, and BST inputs to the CEA were similarly recruited across conditions. There were no sex differences in activation of any of the pathways analyzed. These results suggest that the PVTp-CEA and CA1-CEA pathways underlie feeding inhibition during novelty and could be potential sites of malfunction in excessive food avoidance.
... The insula, as a key structure of the interoceptive network and with reciprocal anatomical connections with the hypothalamus (Allen et al., 1991), has been implicated in regulating sleep and wakefulness (Elvsashagen et al., 2019;Krause et al., 2017). Smaller gray matter volumes of the right insula were noted in individuals with more deficient sleep (Sung et al., 2020). ...
Background
Deficient sleep is implicated in nicotine dependence as well as depressive and anxiety disorders. The hypothalamus regulates the sleep-wake cycle and supports motivated behavior, and hypothalamic dysfunction may underpin comorbid nicotine dependence, depression and anxiety. We aimed to investigate whether and how the resting state functional connectivities (rsFCs) of the hypothalamus relate to cigarette smoking, deficient sleep, depression and anxiety.
Methods
We used the data of 64 smokers and 198 age- and sex-matched adults who never smoked, curated from the Human Connectome Project. Deficient sleep and psychiatric problems were each assessed with Pittsburgh Sleep Quality Index (PSQI) and Achenbach Adult Self-Report. We processed the imaging data with published routines and evaluated the results at a corrected threshold, all with age, sex, and the severity of alcohol use as covariates.
Results
Smokers vs. never smokers showed poorer sleep quality and greater severity of depression and anxiety. In smokers only, the total PSQI score, indicating more sleep deficits, was positively associated with hypothalamic rsFCs with the right inferior frontal/insula/superior temporal and postcentral (rPoCG) gyri. Stronger hypothalamus-rPoCG rsFCs were also associated with greater severity of depression and anxiety in smokers but not never smokers. Additionally, in smokers, the PSQI score completely mediated the relationships of hypothalamus-rPoCG rsFCs with depression and anxiety severity.
Conclusions
These findings associate hypothalamic circuit dysfunction to sleep deficiency and severity of depression and anxiety symptoms in adults who smoke. Future studies may investigate the roles of the hypothalamic circuit in motivated behaviors to better characterize the inter-related neural markers of smoking, deficient sleep, depression and anxiety.
... found both in rats and humans [31][32][33][34][35][36] -support a possible role of these structures in the integration of autonomic responses during ongoing behavior. This study investigated the roles of AIC and PL in temporal decisionmaking. ...
... Studies have shown that both PL and AIC are high-order structures involved in decision-making and time perception [21,25,[44][45][46][47]. Also, some authors suggest a role for these regions in the integration of autonomic responses with ongoing behavior [31,32,36]. In this study, we investigated the role of PL and AIC in switch latency and variability in a switch task. ...
... In the literature, the caudal insular region, specifically the posterior agranular insular cortex, is considered responsible for arterial pressure regulation in rats [117], but our study did not reveal altered binding densities to D1 dopamine receptors (D1DR) or D2 dopamine receptors (D2DR) in this region ( Figures 3H and 4H). In general, the granular and dysgranular insular cortices are referred to as the primary interoceptive cortex [118], and the agranular regions of the insular cortex are referred to as the association sensory cortex [118,119]. We might hypothesize that the interoception is rather dysfunctional in KM rats. ...
... In the literature, the caudal insular region, specifically the posterior agranular insular cortex, is considered responsible for arterial pressure regulation in rats [117], but our study did not reveal altered binding densities to D1 dopamine receptors (D1DR) or D2 dopamine receptors (D2DR) in this region ( Figures 3H and 4H). In general, the granular and dysgranular insular cortices are referred to as the primary interoceptive cortex [118], and the agranular regions of the insular cortex are referred to as the association sensory cortex [118,119]. We might hypothesize that the interoception is rather dysfunctional in KM rats. ...
The involvement of the prefrontal cortical dopaminergic system in the psychopathology of epilepsies and comorbid conditions such as autism spectrum disorder (ASD) still needs to be explored. We used autoradiography to study the D1-like (D1DR) and D2-like (D2DR) receptor binding density in the prefrontal cortex of normal Wistar rats and Wistar-derived strains with generalized convulsive and/or non-convulsive epilepsy. WAG/Rij rats served as a model for non-convulsive absence epilepsy, WAG/Rij-AGS as a model of mixed convulsive/non-convulsive form, and KM strain was a model for convulsive epilepsy comorbid with an ASD-like behavioral phenotype. The prefrontal cortex of rats with any epileptic pathology studied demonstrated profound decreases in binding densities to both D1DR and D2DR; the effects were localized in the primary and secondary anterior cingulate cortices, and adjacent regions. The local decreased D1DR and D2DR binding densities were independent of (not correlated with) each other. The particular group of epileptic rats with an ASD-like phenotype (KM strain) displayed changes in the lateral prefrontal cortex: D1DR were lowered, whereas D2DR were elevated, in the dysgranular insular cortex and adjacent regions. Thus, epilepsy-related changes in the dopaminergic system of the rat archeocortex were localized in the medial prefrontal regions, whereas ASD-related changes were seen in the lateral prefrontal aspects. The findings point to putative local dopaminergic dysfunctions, associated with generalized epilepsies and/or ASD.
... We interpret the importance of the insula to social affective behaviors as a consequence of its interconnections with the network of highly conserved brain regions that orchestrate social behavior [40] and our recent work has addressed the necessity of this connectivity. The basolateral amygdala (BLA) is a key component of several network models of social cognition including the Social Decision Making Network [41] and "social brain" [42] and sends a dense fiber input to the posterior insula [43,44]. BLA neurons are remarkably sensitive to conspecific behavior [45]; respond during direct observation of a conspecific receiving shock [46]; and are activated upon exposure to a stressed conspecific [47,48]. ...
The ability to detect, appraise, and respond to another’s emotional state is essential to social affective behavior. This is mediated by a network of brain regions responsible for integrating external cues with internal states to orchestrate situationally appropriate behavioral responses. The basolateral amygdala (BLA) and the insular cortex are reciprocally connected regions involved in social cognition and prior work in male rats revealed their contributions to social affective behavior. We investigated the functional role of these regions in female rats in a social affective preference (SAP) test in which experimental rats approach stressed juvenile but avoid stressed adult conspecifics. In separate experiments, the BLA or the insula were inhibited by local infusion of muscimol (100ng/side in 0.5μL saline) or vehicle prior to SAP tests. In both regions, muscimol interfered with preference for the stressed juvenile and naive adult, indicating that these regions are necessary for appropriate social affective behavior. In male rats, SAP behavior requires insular oxytocin but there are noteworthy sex differences in the oxytocin receptor distribution in rats. Oxytocin (500nM) administered to the insula did not alter social behavior but oxytocin infusions to the BLA increased social interaction. In sum, female rats appear to use the same BLA and insula regions for social affective behavior but sex differences exist in contribution of oxytocin in the insula.
... In literature, more caudal insular region (namely, posterior agranular insular cortex) is referred as responsible for arterial pressure in rats [52], which was not marked by altered binding densities to D1DR or D2DR in our study (Figures 3H and 4H). Taking in mind that in general, the granular and dysgranular insular cortices are considered as the primary interoceptive cortex [53], and agranular regions of insular cortex are referred as association sensory cortex [53][54][55], we might hypothesize that interception is rather dysfunctional in KM rats. It doesn't contradict with a putative involvement of insular dopaminergic system in pathophysiology of social deficits in KM rats, since interoception is aberrant in ASD patients [56]. ...
... In literature, more caudal insular region (namely, posterior agranular insular cortex) is referred as responsible for arterial pressure in rats [52], which was not marked by altered binding densities to D1DR or D2DR in our study (Figures 3H and 4H). Taking in mind that in general, the granular and dysgranular insular cortices are considered as the primary interoceptive cortex [53], and agranular regions of insular cortex are referred as association sensory cortex [53][54][55], we might hypothesize that interception is rather dysfunctional in KM rats. It doesn't contradict with a putative involvement of insular dopaminergic system in pathophysiology of social deficits in KM rats, since interoception is aberrant in ASD patients [56]. ...
The involvement of the prefrontal cortical dopaminergic system in psychopathology of epilepsies and comorbid conditions such as autism spectrum disorder (ASD) still needs to be explored. We used autoradiography to study the D1-like (D1DR) and D2-like (D2DR) receptor binding density in the prefrontal cortex of normal Wistar rats and Wistar-derived strains with generalized convulsive and/or nonconvulsive epilepsies. WAG/Rij rats served as a model for non-convulsive absence epilepsy, WAG/Rij-AGS as a model of mixed convulsive/non-convulsive forms, and KM strain was a model for convulsive epilepsy comorbiding with ASD-like behavioral phenotype. Prefrontal cortex of rats with any of epileptic pathology studied, demonstrated profound decreases in binding densities to both D1DR, D2DR; the effects were localized in the primary and secondary anterior cingulate cortexi, and adjacent regions. The local decreased D1DR and D2DR binding densities were independent (not correlated) from each other. The particular group of epileptic rats with ASD-like phenotype (KM strain), displayed changes in the lateral prefrontal cortex and adjacent regions: D1DR were lowered, but those to D2DR elevated, in anterior dysgranular insular cortex and adjacent regions. Thus, epilepsy-related changes in the dopaminergic system of rat archeocortex were localized in the medial regions, whereas ASD-related candidates were seen in the lateral aspects. The findings point to putative local dopaminergic dysfunctions, associated with generalized epilepsies and/or ASD.
... In the current study, the FG labeled neurons were distributed selectively within the AId. Prior work investigated anterior and posterior AI regions, which contains AId (Allen et al., 1991;Shi & Cassell, 1998). The FG neurons within the AId were concentrated in layer 2-3, with sparse labelling in layer 1 and 5. Projections to CEA from AId layer 2-3 implicates early sensory information processing. ...
It is adaptive to restrict eating under uncertainty, such as during habituation to novel foods and unfamiliar environments. However, sustained restrictive eating is a core symptom of eating disorders and has serious long-term health consequences. Current therapeutic efforts are limited, because the neural substrates of restrictive eating are poorly understood. Using a model of feeding avoidance under novelty, our recent study identified forebrain activation patterns and found evidence that the central nucleus of the amygdala (CEA) is a core integrating node. The current study analyzed the activity of CEA inputs in male and female rats to determine if specific pathways are recruited during feeding under novelty. Recruitment of direct inputs from the paraventricular nucleus of the thalamus (PVT), the infralimbic cortex (ILA), the agranular insular cortex (AI), the hippocampal ventral field CA1, and the bed nucleus of the stria terminals (BST) was assessed with combined retrograde tract tracing and Fos induction analysis. The study found that during consumption of a novel food in a novel environment, larger number of neurons within the PVTp and the CA1 that send monosynaptic inputs to the CEA were recruited compared to controls that consumed familiar food in a familiar environment. The ILA, AI, and BST inputs to the CEA were similarly recruited across conditions. There were no sex differences in activation of any of the pathways analyzed. These results suggest that the PVTp-CEA and CA1-CEA pathways underlie feeding inhibition during novelty and could be potential sites of malfunction in excessive food avoidance.
... Across species, the IC is subdivided along the rostrocaudal axis into two parts: the anterior insula and the posterior insula. In rodents, the IC is organized into three subdivisions arranged from dorsal to ventral and progressively devoid of the layer 4 granular layer: the granular subdivision, the dysgranular subdivision, and the agranular subdivision (Fig. 3A) [52,54]. The IC forms an anatomic center with reciprocal connections to sensory, emotional, motivational, and cognitive systems, including the sensory and frontal cortices, amygdala, thalamus, and NAc, as well as with neuromodulatory inputs [55]. ...
Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social behaviors, and many different behavioral paradigms have been used for investigating their neural circuit bases. Social behavior is highly vulnerable to brain network dysfunction caused by neurological and neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms of abnormal social behavior and potential therapeutic targets for treatment. In this review, we outline recent progress and key findings on neural circuit mechanisms underlying social behavior, with particular emphasis on rodent studies that monitor and manipulate the activity of specific circuits using modern systems neuroscience approaches. Social behavior is mediated by a distributed brain-wide network among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, and insular cortex (IC)) and subcortical (e.g., nucleus accumbens, basolateral amygdala (BLA), and ventral tegmental area) structures, influenced by multiple neuromodulatory systems (e.g., oxytocin, dopamine, and serotonin). We particularly draw special attention to IC as a unique cortical area that mediates multisensory integration, encoding of ongoing social interaction, social decision-making, emotion, and empathy. Additionally, a synthesis of studies investigating ASD mouse models demonstrates that dysfunctions in mPFC-BLA circuitry and neuromodulation are prominent. Pharmacological rescues by local or systemic (e.g., oral) administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. Future efforts and technological advances will push forward the next frontiers in this field, such as the elucidation of brain-wide network activity and inter-brain neural dynamics during real and virtual social interactions, and the establishment of circuit-based therapy for disorders affecting social functions.
... Among the most predominate inputs to the insula, specifically to the medial and posterior portions, are the amygdala, thalamus, and sensory cortex (Gehrlach et al., 2020). Notably, the reciprocal connectivity between the amygdala and insula has been well documented (Allen et al., 1991;Augustine, 1996;McDonald et al., 1999;Santiago and Shammah-Lagnado, 2005), and this connection is believed to underlie the role of the insula in tastant reinforcement and gustatory valence encoding (Lavi et al., 2018;Schiff et al., 2018;Wang et al., 2018). ...
Alcohol use disorder is complex and multi-faceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry.
Significance Statement
The insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we utilize converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.
