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1.
J Comp Neurol ; 532(5): e25620, 2024 May.
Article in English | MEDLINE | ID: mdl-38733146

ABSTRACT

We used diverse methods to characterize the role of avian lateral spiriform nucleus (SpL) in basal ganglia motor function. Connectivity analysis showed that SpL receives input from globus pallidus (GP), and the intrapeduncular nucleus (INP) located ventromedial to GP, whose neurons express numerous striatal markers. SpL-projecting GP neurons were large and aspiny, while SpL-projecting INP neurons were medium sized and spiny. Connectivity analysis further showed that SpL receives inputs from subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr), and that the SNr also receives inputs from GP, INP, and STN. Neurochemical analysis showed that SpL neurons express ENK, GAD, and a variety of pallidal neuron markers, and receive GABAergic terminals, some of which also contain DARPP32, consistent with GP pallidal and INP striatal inputs. Connectivity and neurochemical analysis showed that the SpL input to tectum prominently ends on GABAA receptor-enriched tectobulbar neurons. Behavioral studies showed that lesions of SpL impair visuomotor behaviors involving tracking and pecking moving targets. Our results suggest that SpL modulates brainstem-projecting tectobulbar neurons in a manner comparable to the demonstrated influence of GP internus on motor thalamus and of SNr on tectobulbar neurons in mammals. Given published data in amphibians and reptiles, it seems likely the SpL circuit represents a major direct pathway-type circuit by which the basal ganglia exerts its motor influence in nonmammalian tetrapods. The present studies also show that avian striatum is divided into three spatially segregated territories with differing connectivity, a medial striato-nigral territory, a dorsolateral striato-GP territory, and the ventrolateral INP motor territory.


Subject(s)
Basal Ganglia , Neural Pathways , Animals , Basal Ganglia/metabolism , Neural Pathways/physiology , Neural Pathways/chemistry , Male , Neurons/metabolism , Globus Pallidus/metabolism , Globus Pallidus/chemistry , Globus Pallidus/anatomy & histology
2.
J Comp Neurol ; 532(5): e25623, 2024 May.
Article in English | MEDLINE | ID: mdl-38803103

ABSTRACT

In Alzheimer´s disease (AD), hyperphosphorylated tau spreads along the cerebral cortex in a stereotypical pattern that parallels cognitive deterioration. Tau seems to spread transsynaptically along cortico-cotical pathways that, according to synaptic tract-tracing studies in nonhuman primates, have specific laminar patterns related to the cortical type of the connected areas. This relation is described in the Structural Model. In the present article, we study the laminar distribution of hyperphosphorylated tau, labeled with the antibody AT8, along temporal cortical types in postmortem human brains with different AD stages to test the predictions of the Structural Model. Brains from donors without dementia had scant AT8-immunorreactive (AT8-ir) neurons in allo-, meso-, and isocortical types. In early AD stages, the mesocortical dysgranular type, including part of the transentorhinal cortex, had the highest AT8 immunostaining and AT8-ir neurons density. In advanced AD stages, AT8 immunostaining increased along the isocortical types until reaching the auditory koniocortex. Regarding laminar patterns, in early AD stages there were more AT8-ir neurons in supragranular layers in each de novo involved neocortical type; in advanced AD stages, AT8-ir neurons were equally distributed in supra- and infragranular layers. These AT8-ir laminar patterns are compatible with the predictions of the Structural Model. In summary, we show that hyperphosphorylated tau initially accumulates in allo-, meso-, and isocortical types, offer a proof of concept for the validity of the Structural Model to predict synaptic pathway organization in the human cerebral cortex, and highlight the relevance of nonhuman primate tract-tracing studies to understand human neuropathology.


Subject(s)
Alzheimer Disease , Cerebral Cortex , Neural Pathways , tau Proteins , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Humans , tau Proteins/metabolism , Male , Female , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Aged , Phosphorylation , Aged, 80 and over , Neural Pathways/metabolism , Neural Pathways/pathology , Neural Pathways/chemistry , Middle Aged , Models, Neurological , Neurons/metabolism , Neurons/pathology
3.
Nat Neurosci ; 24(6): 873-885, 2021 06.
Article in English | MEDLINE | ID: mdl-33972801

ABSTRACT

Functional circuits consist of neurons with diverse axonal projections and gene expression. Understanding the molecular signature of projections requires high-throughput interrogation of both gene expression and projections to multiple targets in the same cells at cellular resolution, which is difficult to achieve using current technology. Here, we introduce BARseq2, a technique that simultaneously maps projections and detects multiplexed gene expression by in situ sequencing. We determined the expression of cadherins and cell-type markers in 29,933 cells and the projections of 3,164 cells in both the mouse motor cortex and auditory cortex. Associating gene expression and projections in 1,349 neurons revealed shared cadherin signatures of homologous projections across the two cortical areas. These cadherins were enriched across multiple branches of the transcriptomic taxonomy. By correlating multigene expression and projections to many targets in single neurons with high throughput, BARseq2 provides a potential path to uncovering the molecular logic underlying neuronal circuits.


Subject(s)
Auditory Cortex/metabolism , Brain Mapping/methods , Electronic Data Processing/methods , Gene Regulatory Networks/genetics , Motor Cortex/metabolism , Animals , Auditory Cortex/chemistry , Male , Mice , Mice, Inbred C57BL , Motor Cortex/chemistry , Neural Pathways/chemistry , Neural Pathways/metabolism
4.
J Comp Neurol ; 529(9): 2243-2264, 2021 06.
Article in English | MEDLINE | ID: mdl-33340092

ABSTRACT

Eupnea is generated by neural circuits located in the ponto-medullary brainstem, but can be modulated by higher brain inputs which contribute to volitional control of breathing and the expression of orofacial behaviors, such as vocalization, sniffing, coughing, and swallowing. Surprisingly, the anatomical organization of descending inputs that connect the forebrain with the brainstem respiratory network remains poorly defined. We hypothesized that descending forebrain projections target multiple distributed respiratory control nuclei across the neuroaxis. To test our hypothesis, we made discrete unilateral microinjections of the retrograde tracer cholera toxin subunit B in the midbrain periaqueductal gray (PAG), the pontine Kölliker-Fuse nucleus (KFn), the medullary Bötzinger complex (BötC), pre-BötC, or caudal midline raphé nuclei. We quantified the regional distribution of retrogradely labeled neurons in the forebrain 12-14 days postinjection. Overall, our data reveal that descending inputs from cortical areas predominantly target the PAG and KFn. Differential forebrain regions innervating the PAG (prefrontal, cingulate cortices, and lateral septum) and KFn (rhinal, piriform, and somatosensory cortices) imply that volitional motor commands for vocalization are specifically relayed via the PAG, while the KFn may receive commands to coordinate breathing with other orofacial behaviors (e.g., sniffing, swallowing). Additionally, we observed that the limbic or autonomic (interoceptive) systems are connected to broadly distributed downstream bulbar respiratory networks. Collectively, these data provide a neural substrate to explain how volitional, state-dependent, and emotional modulation of breathing is regulated by the forebrain.


Subject(s)
Medulla Oblongata/physiology , Mesencephalon/physiology , Neurons/physiology , Pons/physiology , Prosencephalon/physiology , Respiratory Mechanics/physiology , Animals , Female , Male , Medulla Oblongata/chemistry , Mesencephalon/chemistry , Microinjections/methods , Neural Pathways/chemistry , Neural Pathways/physiology , Neurons/chemistry , Pons/chemistry , Prosencephalon/chemistry , Radioactive Tracers , Rats , Rats, Sprague-Dawley
5.
Article in English | MEDLINE | ID: mdl-32890694

ABSTRACT

Depression is a severe and chronic mental disorder that affects millions of individuals worldwide. Symptoms include depressed mood, loss of interest, reduced motivation and suicidal thoughts. Even though findings from genetic, molecular and imaging studies have helped provide some clues regarding the mechanisms underlying depression-like behaviors, there are still many unanswered questions that need to be addressed. Optogenetics, a technique developed in the early 2000s, has proved effective in the study and treatment of depression and depression-like behaviors and has revolutionized already known experimental techniques. This technique employs light and genetic tools to either inhibit or excite specific neurons or pathways within the brain. In this review paper, an up-to-date understanding of the use of optogenetics in the study of depression-like behaviors is provided, along with suggestions for future research directions.


Subject(s)
Brain Chemistry , Brain , Depression/diagnosis , Depression/genetics , Neurons/chemistry , Optogenetics/methods , Animals , Brain/physiology , Brain Chemistry/physiology , Humans , Neural Pathways/chemistry , Neural Pathways/physiology , Neurons/physiology , Optogenetics/trends
6.
Cereb Cortex ; 31(4): 2169-2186, 2021 03 05.
Article in English | MEDLINE | ID: mdl-33251536

ABSTRACT

In a changing environment, organisms need to decide when to select items that resemble previously rewarded stimuli and when it is best to switch to other stimulus types. Here, we used chemogenetic techniques to provide causal evidence that activity in the rodent anterior cingulate cortex and its efferents to the anterior thalamic nuclei modulate the ability to attend to reliable predictors of important outcomes. Rats completed an attentional set-shifting paradigm that first measures the ability to master serial discriminations involving a constant stimulus dimension that reliably predicts reinforcement (intradimensional-shift), followed by the ability to shift attention to a previously irrelevant class of stimuli when reinforcement contingencies change (extradimensional-shift). Chemogenetic disruption of the anterior cingulate cortex (Experiment 1) as well as selective disruption of anterior cingulate efferents to the anterior thalamic nuclei (Experiment 2) impaired intradimensional learning but facilitated 2 sets of extradimensional-shifts. This pattern of results signals the loss of a corticothalamic system for cognitive control that preferentially processes stimuli resembling those previously associated with reward. Previous studies highlight a separate medial prefrontal system that promotes the converse pattern, that is, switching to hitherto inconsistent predictors of reward when contingencies change. Competition between these 2 systems regulates cognitive flexibility and choice.


Subject(s)
Anterior Thalamic Nuclei/metabolism , Attention/physiology , Gyrus Cinguli/metabolism , Optogenetics/methods , Reward , Adenoviridae/metabolism , Animals , Anterior Thalamic Nuclei/chemistry , Anterior Thalamic Nuclei/drug effects , Attention/drug effects , Discrimination Learning/drug effects , Discrimination Learning/physiology , Gyrus Cinguli/chemistry , Gyrus Cinguli/drug effects , Injections, Intraventricular , Male , Neural Pathways/chemistry , Neural Pathways/drug effects , Neural Pathways/metabolism , Piperazines/administration & dosage , Piperazines/analysis , Piperazines/metabolism , Rats
7.
J Comp Neurol ; 529(4): 885-904, 2021 03.
Article in English | MEDLINE | ID: mdl-32677044

ABSTRACT

The anterior cingulate cortex (ACC) is important for decision-making as it integrates motor plans with affective and contextual limbic information. Disruptions in these networks have been observed in depression, bipolar disorder, and post-traumatic stress disorder. Yet, overlap of limbic and motor connections within subdivisions of the ACC is not well understood. Hence, we administered a combination of retrograde and anterograde tracers into structures important for contextual memories (entorhinal cortex), affective processing (amygdala), and motor planning (dorsal premotor cortex) to assess overlap of labeled projection neurons from (outputs) and axon terminals to (inputs) the ACC of adult rhesus monkeys (Macaca mulatta). Our data show that entorhinal and dorsal premotor cortical (dPMC) connections are segregated across ventral (A25, A24a) and dorsal (A24b,c) subregions of the ACC, while amygdalar connections are more evenly distributed across subregions. Among all areas, the rostral ACC (A32) had the lowest relative density of connections with all three regions. In the ventral ACC, entorhinal and amygdalar connections strongly overlap across all layers, especially in A25. In the dorsal ACC, outputs to dPMC and the amygdala strongly overlap in deep layers. However, dPMC input to the dorsal ACC was densest in deep layers, while amygdalar inputs predominantly localized in upper layers. These connection patterns are consistent with diverse roles of the dorsal ACC in motor evaluation and the ventral ACC in affective and contextual memory. Further, distinct laminar circuits suggest unique interactions within specific ACC compartments that are likely important for the temporal integration of motor and limbic information during flexible goal-directed behavior.


Subject(s)
Amygdala/anatomy & histology , Entorhinal Cortex/anatomy & histology , Gyrus Cinguli/anatomy & histology , Prefrontal Cortex/anatomy & histology , Amygdala/chemistry , Amygdala/cytology , Animals , Entorhinal Cortex/chemistry , Entorhinal Cortex/cytology , Female , Gyrus Cinguli/chemistry , Gyrus Cinguli/cytology , Macaca mulatta , Male , Neural Pathways/anatomy & histology , Neural Pathways/chemistry , Neural Pathways/cytology , Prefrontal Cortex/chemistry , Prefrontal Cortex/cytology
8.
J Comp Neurol ; 529(4): 828-852, 2021 03.
Article in English | MEDLINE | ID: mdl-32656783

ABSTRACT

The organization of projections from the macaque monkey hippocampus, subiculum, presubiculum, and parasubiculum to the entorhinal cortex was analyzed using anterograde and retrograde tracing techniques. Projections exclusively originate in the CA1 field of the hippocampus and in the subiculum, presubiculum, and parasubiculum. The CA1 and subicular projections terminate most densely in Layers V and VI of the entorhinal cortex, with sparser innervation of the deep portion of Layers III and II. Entorhinal projections from CA1 and the subiculum are topographically organized such that a rostrocaudal axis of origin is related to a medial-to-lateral axis of termination. A proximodistal axis of origin in CA1 and distoproximal axis in subiculum are related to a rostrocaudal axis of termination in the entorhinal cortex. The presubiculum sends a dense, bilateral projection to caudal parts of the entorhinal cortex. This projection terminates most densely in Layer III with sparser termination in Layers I, II, and V. The same parts of entorhinal cortex receive a dense projection from the parasubiculum. This projection terminates in Layers III and II. Both presubicular and parasubicular projections demonstrate the same longitudinal topographic organization as the projections from CA1 and the subiculum. These studies demonstrate that: (a) hippocampal and subicular inputs to the entorhinal cortex in the monkey are organized similar to those described in nonprimate species; (b) the topographic organization of the projections from the hippocampus and subicular areas matches that of the reciprocal projections from the entorhinal cortex to the hippocampus and the subicular areas.


Subject(s)
Entorhinal Cortex/chemistry , Entorhinal Cortex/cytology , Hippocampus/chemistry , Hippocampus/cytology , Parahippocampal Gyrus/chemistry , Parahippocampal Gyrus/cytology , Animals , Female , Haplorhini , Macaca fascicularis , Male , Neural Pathways/chemistry , Neural Pathways/cytology
9.
Neuropharmacology ; 178: 108270, 2020 11 01.
Article in English | MEDLINE | ID: mdl-32795460

ABSTRACT

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced in the lateral hypothalamus and zona incerta that increases food intake. The neuronal pathways and behavioral mechanisms mediating the orexigenic effects of MCH are poorly understood, as is the extent to which MCH-mediated feeding outcomes are sex-dependent. Here we investigate the hypothesis that MCH-producing neurons act in the nucleus accumbens shell (ACBsh) to promote feeding behavior and motivation for palatable food in a sex-dependent manner. We utilized ACBsh MCH receptor (MCH1R)-directed pharmacology as well as a dual virus chemogenetic approach to selectively activate MCH neurons that project to the ACBsh. Results reveal that both ACBsh MCH1R activation and activating ACBsh-projecting MCH neurons increase consumption of standard chow and palatable sucrose in male rats without affecting motivated operant responding for sucrose, general activity levels, or anxiety-like behavior. In contrast, food intake was not affected in female rats by either ACBsh MCH1R activation or ACBsh-projecting MCH neuron activation. To determine a mechanism for this sexual dimorphism, we investigated whether the orexigenic effect of ACBsh MCH1R activation is reduced by endogenous estradiol signaling. In ovariectomized female rats on a cyclic regimen of either estradiol (EB) or oil vehicle, ACBsh MCH1R activation increased feeding only in oil-treated rats, suggesting that EB attenuates the ability of ACBsh MCH signaling to promote food intake. Collective results show that MCH ACBsh signaling promotes feeding in an estrogen- and sex-dependent manner, thus identifying novel neurobiological mechanisms through which MCH and female sex hormones interact to influence food intake.


Subject(s)
Feeding Behavior/physiology , Hypothalamic Hormones/metabolism , Melanins/metabolism , Nucleus Accumbens/metabolism , Pituitary Hormones/metabolism , Sex Characteristics , Signal Transduction/physiology , Animals , Feeding Behavior/psychology , Female , Hypothalamic Hormones/analysis , Male , Melanins/analysis , Neural Pathways/chemistry , Neural Pathways/metabolism , Nucleus Accumbens/chemistry , Pituitary Hormones/analysis , Rats , Rats, Sprague-Dawley
10.
Neuroimage ; 223: 117309, 2020 12.
Article in English | MEDLINE | ID: mdl-32861788

ABSTRACT

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults.


Subject(s)
Cerebral Cortex/chemistry , Cerebral Cortex/physiology , Iron/analysis , Memory, Short-Term/physiology , Aged , Aged, 80 and over , Brain Mapping , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neural Pathways/chemistry , Neural Pathways/physiology , Spin Labels
11.
J Neurosci ; 40(30): 5785-5796, 2020 07 22.
Article in English | MEDLINE | ID: mdl-32532890

ABSTRACT

The cerebral cortex, with all its computational power, can only influence behavior via corticofugal connections originating from layer 5 (L5) cells (Sherman and Guillery, 2013). To begin to establish the global pattern of these outputs, we examined L5 efferents originating from four cortical areas: somatosensory, visual, motor, and prefrontal (i.e., ventromedial orbitofrontal) cortex. We injected Cre-dependent adeno-associated virus in an Rbp4-Cre transgenic mouse line (both sexes) to label these L5 efferents selectively. Our study reveals that, across this diverse series of cortical regions, L5 commonly projects to multiple thalamic and extrathalamic sites. We also identified several novel corticofugal targets (i.e., the lateral dorsal nucleus, submedial nucleus) previously unidentified as L5 targets. We identified common patterns for these projections: all areas innervated both thalamus and the midbrain, and all areas innervated multiple thalamic targets, including those with core and matrix cell types (Jones, 1998). An examination of the terminal size within each of these targets suggests that terminal populations of L5 efferents are not consistently large but vary with cortical area and target; and in some cases, these include small terminals only. Overall, our data reveal more widespread and diverse L5 efferents than previously appreciated, suggesting a generalizable role for this cortical layer in influencing motor commands and cognitive processes.SIGNIFICANCE STATEMENT While the neocortex is responsible for coordination of complex behavior, it requires communication with subcortical regions to do so. It is specifically cortical layer 5 (L5) that is thought to underlie these behaviors, although it is unknown whether this holds true across functionally different cortical areas. Using a selective viral tracing method and transgenic mice, we examined the connectivity of four cortical regions (somatosensory, visual, motor and prefrontal cortex) to assess the generalizability of these L5 projections. All areas of cortex projected to overlapping as well as distinct thalamic and brainstem structures. Terminals within these regions varied in size, implicating that L5 has a broad and diverse impact on behavior.


Subject(s)
Cerebral Cortex/chemistry , Cerebral Cortex/physiology , Thalamus/chemistry , Thalamus/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Pathways/chemistry , Neural Pathways/physiology
12.
Brain Res ; 1741: 146872, 2020 08 15.
Article in English | MEDLINE | ID: mdl-32360868

ABSTRACT

Melanin-concentrating hormone (MCH) is a neuropeptide primarily transcribed in the lateral hypothalamus (LH), with vast projections to many areas throughout the central nervous system that play an important role in motivated behaviors and drug use. Anatomical, pharmacological and genetic studies implicate MCH in mediating the intake and reinforcement of commonly abused substances, acting by influencing several systems including the mesolimbic dopaminergic system, glutamatergic as well as GABAergic signaling and being modulated by inflammatory neuroimmune pathways. Further support for the role of MCH in controlling behavior related to drug use will be discussed as it relates to cerebral ventricular volume transmission and intracellular molecules including cocaine- and amphetamine-regulated transcript peptide, dopamine- and cAMP-regulated phosphoprotein 32 kDa. The primary goal of this review is to introduce and summarize current literature surrounding the role of MCH in mediating the intake and reinforcement of commonly abused drugs, such as alcohol, cocaine, amphetamine, nicotine and opiates.


Subject(s)
Brain/metabolism , Hypothalamic Hormones/metabolism , Melanins/metabolism , Neuroimmunomodulation/physiology , Pituitary Hormones/metabolism , Substance-Related Disorders/metabolism , Substance-Related Disorders/psychology , Animals , Brain Chemistry , Humans , Hypothalamic Hormones/analysis , Melanins/analysis , Neural Pathways/chemistry , Neural Pathways/metabolism , Neurons/chemistry , Neurons/metabolism , Neuropeptides/analysis , Neuropeptides/metabolism , Pituitary Hormones/analysis
13.
Front Neural Circuits ; 14: 11, 2020.
Article in English | MEDLINE | ID: mdl-32296310

ABSTRACT

Objective: To investigate whether the CSF-contacting nucleus receives brainstem and spinal cord projections and to understand the functional significance of these connections. Methods: The retrograde tracer cholera toxin B subunit (CB) was injected into the CSF-contacting nucleus in Sprague-Dawley rats according the previously reported stereotaxic coordinates. After 7-10 days, these rats were perfused and their brainstem and spinal cord were sliced (thickness, 40 µm) using a freezing microtome. All the sections were subjected to CB immunofluorescence staining. The distribution of CB-positive neuron in different brainstem and spinal cord areas was observed under fluorescence microscope. Results: The retrograde labeled CB-positive neurons were found in the midbrain, pons, medulla oblongata, and spinal cord. Four functional areas including one hundred and twelve sub-regions have projections to the CSF-contacting nucleus. However, the density of CB-positive neuron distribution ranged from sparse to dense. Conclusion: Based on the connectivity patterns of the CSF-contacting nucleus receives anatomical inputs from the brainstem and spinal cord, we preliminarily conclude and summarize that the CSF-contacting nucleus participates in pain, visceral activity, sleep and arousal, emotion, and drug addiction. The present study firstly illustrates the broad projections of the CSF-contacting nucleus from the brainstem and spinal cord, which implies the complicated functions of the nucleus especially for the unique roles of coordination in neural and body fluids regulation.


Subject(s)
Brain Stem/chemistry , Cerebrospinal Fluid/chemistry , Connectome/methods , Imaging, Three-Dimensional/methods , Spinal Cord/chemistry , Abducens Nucleus/chemistry , Abducens Nucleus/cytology , Abducens Nucleus/physiology , Animals , Brain Stem/cytology , Brain Stem/physiology , Cerebral Aqueduct/chemistry , Cerebral Aqueduct/cytology , Cerebral Aqueduct/physiology , Cerebrospinal Fluid/physiology , Neural Pathways/chemistry , Neural Pathways/cytology , Neural Pathways/physiology , Rats , Rats, Sprague-Dawley , Spinal Cord/cytology , Spinal Cord/physiology , Vestibular Nuclei/chemistry , Vestibular Nuclei/cytology , Vestibular Nuclei/physiology
14.
Neuropharmacology ; 168: 108028, 2020 05 15.
Article in English | MEDLINE | ID: mdl-32151646

ABSTRACT

Itch is an unpleasant feeling that triggers scratching behavior. Much progress has been made in identifying the mechanism of itch at the peripheral and spinal levels, however, itch circuits in the brain remain largely unexplored. We previously found that anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) inputs modulated histamine-induced itch sensation, but how itch information was transmitted to ACC remained unclear. Here, we demonstrated that the anteromedial thalamic nucleus (AM) was activated during histaminergic itch, and there existed reciprocal neuronal projections between AM and ACC. Disconnection between AM and ACC resulted in a significant reduction of histaminergic, but not nonhistaminergic, itch-related scratching behavior. Optogenetic activation of AM-ACC, but not ACC-AM, projections evoked histaminergic itch sensation. Thus, our studies firstly reveal that AM is critical for histaminergic itch sensation and AM-ACC projections modulate histaminergic itch-induced scratching behavior.


Subject(s)
Anterior Thalamic Nuclei/metabolism , Gyrus Cinguli/metabolism , Histamine/metabolism , Pruritus/metabolism , Sensation/physiology , Animals , Anterior Thalamic Nuclei/chemistry , Gyrus Cinguli/chemistry , Histamine/analysis , Male , Mice , Mice, Inbred C57BL , Neural Pathways/chemistry , Neural Pathways/metabolism , Optogenetics/methods , Pruritus/diagnosis
15.
J Comp Neurol ; 528(3): 453-467, 2020 02 15.
Article in English | MEDLINE | ID: mdl-31483857

ABSTRACT

Continuing investigations of corticostriatal connections in rodents emphasize an intricate architecture where striatal projections originate from different combinations of cortical layers, include an inhibitory component, and form terminal arborizations which are cell-type dependent, extensive, or compact. Here, we report that in macaque monkeys, deep and superficial cortical white matter neurons (WMNs), peri-claustral WMNs, and the claustrum proper project to the putamen. WMNs retrogradely labeled by injections in the putamen (four injections in three macaques) were widely distributed, up to 10 mm antero-posterior from the injection site, mainly dorsal to the putamen in the external capsule, and below the premotor cortex. Striatally projecting labeled WMNs (WMNsST) were heterogeneous in size and shape, including a small GABAergic component. We compared the number of WMNsST with labeled claustral and cortical neurons and also estimated their proportion in relation to total WMNs. Since some WMNsST were located adjoining the claustrum, we wanted to compare results for density and distribution of striatally projecting claustral neurons (ClaST). ClaST neurons were morphologically heterogeneous and mainly located in the dorsal and anterior claustrum, in regions known to project to frontal, motor, and cingulate cortical areas. The ratio of ClaST to WMNsST was about 4:1 averaged across the four injections. These results provide new specifics on the connectional networks of WMNs in nonhuman primates, and delineate additional loops in the corticostriatal architecture, consisting of interconnections across cortex, claustralstriatal and striatally projecting WMNs.


Subject(s)
Claustrum/physiology , Nerve Net/physiology , Neurons/physiology , Putamen/physiology , White Matter/physiology , Animals , Claustrum/chemistry , Female , Macaca , Macaca mulatta , Male , Nerve Net/chemistry , Neural Pathways/chemistry , Neural Pathways/physiology , Neurons/chemistry , Putamen/chemistry , White Matter/chemistry
16.
Neuropsychopharmacology ; 45(4): 579-588, 2020 03.
Article in English | MEDLINE | ID: mdl-31593982

ABSTRACT

Compulsive eating characterizes many binge-related eating disorders, yet its neurobiological basis is poorly understood. The insular cortex subserves visceral-emotional functions, including taste processing, and is implicated in drug craving and relapse. Here, via optoinhibition, we implicate projections from the anterior insular cortex to the nucleus accumbens as modulating highly compulsive-like food self-administration behaviors that result from intermittent access to a palatable, high-sucrose diet. We identified compulsive-like eating behavior in female rats through progressive ratio schedule self-administration and punishment-resistant responding, food reward tolerance and escalation of intake through 24-h energy intake and fixed-ratio operant self-administration sessions, and withdrawal-like irritability through the bottle brush test. We also identified an endocrine profile of heightened GLP-1 and PP but lower ghrelin that differentiated rats with the most compulsive-like eating behavior. Measures of compulsive eating severity also directly correlated to leptin, body weight and adiposity. Collectively, this novel model of compulsive-like eating symptoms demonstrates adaptations in insula-ventral striatal circuitry and metabolic regulatory hormones that warrant further study.


Subject(s)
Cerebral Cortex/physiopathology , Feeding Behavior/physiology , Food Addiction/physiopathology , Nerve Net/physiopathology , Ventral Striatum/physiopathology , Animals , Cerebral Cortex/chemistry , Compulsive Behavior/physiopathology , Compulsive Behavior/psychology , Conditioning, Operant/physiology , Feeding Behavior/psychology , Female , Food Addiction/psychology , Nerve Net/chemistry , Neural Pathways/chemistry , Neural Pathways/physiopathology , Optogenetics/methods , Rats , Rats, Wistar , Time Factors , Ventral Striatum/chemistry
17.
J Neurosci ; 39(47): 9369-9382, 2019 11 20.
Article in English | MEDLINE | ID: mdl-31597726

ABSTRACT

Conditioned taste aversion (CTA) is an associative learning paradigm, wherein consumption of an appetitive tastant (e.g., saccharin) is paired to the administration of a malaise-inducing agent, such as intraperitoneal injection of LiCl. Aversive taste learning and retrieval require neuronal activity within the anterior insula (aIC) and the basolateral amygdala (BLA). Here, we labeled neurons of the aIC projecting to the BLA in adult male mice using a retro-AAV construct and assessed their necessity in aversive and appetitive taste learning. By restricting the expression of chemogenetic receptors in aIC-to-BLA neurons, we demonstrate that activity within the aIC-to-BLA projection is necessary for both aversive taste memory acquisition and retrieval, but not for its maintenance, nor its extinction. Moreover, inhibition of the projection did not affect incidental taste learning per se, but effectively suppressed aversive taste memory retrieval when applied either during or before the encoding of the unconditioned stimulus for CTA (i.e., malaise). Remarkably, activation of the projection after novel taste consumption, without experiencing any internal discomfort, was sufficient to form an artificial aversive taste memory, resulting in strong aversive behavior upon retrieval. Our results indicate that aIC-to-BLA projecting neurons are an essential component in the ability of the brain to associate taste sensory stimuli with body states of negative valence and guide the expression of valence-specific behavior upon taste memory retrieval.SIGNIFICANCE STATEMENT In the present study we subjected mice to the conditioned taste aversion paradigm, where animals learn to associate novel taste with malaise (i.e., assign it negative valence). We show that activation of neurons in the anterior insular cortex (aIC) that project into the basolateral amygdala (BLA) in response to conditioned taste aversion is necessary to form a memory for a taste of negative valence. Moreover, artificial activation of this pathway (without any feeling of pain) after the sampling of a taste can also lead to such associative memory. Thus, activation of aIC-to-BLA projecting neurons is necessary and sufficient to form and retrieve aversive taste memory.


Subject(s)
Amygdala/physiology , Avoidance Learning/physiology , Basolateral Nuclear Complex/physiology , Neurons/physiology , Taste/physiology , Amygdala/chemistry , Animals , Basolateral Nuclear Complex/chemistry , Male , Mice , Neural Pathways/chemistry , Neural Pathways/physiology , Neurons/chemistry , Organ Culture Techniques , Random Allocation
18.
J Comp Neurol ; 527(18): 3046-3072, 2019 12 15.
Article in English | MEDLINE | ID: mdl-31199515

ABSTRACT

The laterodorsal tegmental nucleus (LDTg) is a hindbrain cholinergic cell group thought to be involved in mechanisms of arousal and the control of midbrain dopamine cells. Nowadays, there is increasing evidence that LDTg is also engaged in mechanisms of anxiety/fear and promotion of emotional arousal under adverse conditions. Interestingly, LDTg appears to be connected with other regulators of aversive motivational states, including the lateral habenula (LHb), medial habenula (MHb), interpeduncular nucleus (IP), and median raphe nucleus (MnR). However, the circuitry between these structures has hitherto not been systematically investigated. Here, we placed injections of retrograde or anterograde tracers into LDTg, LHb, IP, and MnR. We also examined the transmitter phenotype of LDTg afferents to IP by combining retrograde tracing with immunofluorescence and in situ hybridization techniques. We found LHb inputs to LDTg mainly emerging from the medial division of the LHb (LHbM), which also receives axonal input from LDTg. The bidirectional connections between IP and LDTg displayed a lateralized organization, with LDTg inputs to IP being predominantly GABAergic or cholinergic and mainly directed to the contralateral IP. Moreover, we disclosed reciprocal LDTg connections with structures involved in the modulation of hippocampal theta rhythm including MnR, nucleus incertus, and supramammillary nucleus. Our findings indicate that the habenula is linked with LDTg either by direct reciprocal projections from/to LHbM or indirectly via the MHb-IP axis, supporting a functional role of LDTg in the regulation of aversive behaviors, and further characterizing LHb as a master controller of ascending brainstem state-setting modulatory projection systems.


Subject(s)
Habenula/physiology , Interpeduncular Nucleus/physiology , Raphe Nuclei/physiology , Rhombencephalon/physiology , Animals , Habenula/chemistry , Interpeduncular Nucleus/chemistry , Male , Neural Pathways/chemistry , Neural Pathways/physiology , Neuroanatomical Tract-Tracing Techniques/methods , Raphe Nuclei/chemistry , Rats , Rats, Wistar , Rhombencephalon/chemistry
19.
Neuroscience ; 410: 293-304, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31075313

ABSTRACT

Medullary dorsal horn (MDH), the homolog of spinal dorsal horn, plays essential roles in processing of nociceptive signals from orofacial region toward higher centers, such as the ventral posteromedial thalamic nucleus (VPM) and parafascicular thalamic nucleus (Pf), which belong to the sensory-discriminative and affective aspects of pain transmission systems at the thalamic level, respectively. In the present study, in order to provide morphological evidence for whether neurons in the MDH send collateral projections to the VPM and Pf, a retrograde double tracing method combined with immunofluorescence staining for substance P (SP), SP receptor (SPR) and Fos protein was used. Fluoro-gold (FG) was injected into the VPM and the tetramethylrhodamine-dextran (TMR) was injected into the Pf. The result revealed that both FG- and TMR-labeled projection neurons were observed throughout the entire extent of the MDH, while the FG/TMR double-labeled neurons were mainly located in laminae I and III. It was also found that some of the FG/TMR double-labeled neurons within lamina I expressed SPR and were in close contact with SP-immunoreactive (SP-ir) terminals. After formalin injection into the orofacial region, 41.4% and 34.3% of the FG/TMR double-labeled neurons expressed Fos protein in laminae I and III, respectively. The present results provided morphological evidence for that some SPR-expressing neurons within the MDH send collateral projections to both VPM and Pf and might be involved in sensory-discriminative and affective aspects of acute orofacial nociceptive information transmission.


Subject(s)
Intralaminar Thalamic Nuclei/physiology , Medulla Oblongata/physiology , Spinal Cord Dorsal Horn/physiology , Ventral Thalamic Nuclei/physiology , Animals , Intralaminar Thalamic Nuclei/chemistry , Male , Medulla Oblongata/chemistry , Neural Pathways/chemistry , Neural Pathways/physiology , Rats , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn/chemistry , Ventral Thalamic Nuclei/chemistry
20.
J Comp Neurol ; 527(14): 2291-2301, 2019 10 01.
Article in English | MEDLINE | ID: mdl-30861131

ABSTRACT

Within the supraoptic nucleus (SON) of a 35-day-old rat, we previously demonstrated a collateral sprouting response that reinnervates the partially denervated neural lobe (NL) after unilateral lesion of the hypothalamo-neurohypophysial tract. Others have shown a decreased propensity for axonal sprouting in an aged brain; therefore, to see if the SON exhibits a decreased propensity for axonal sprouting as the animal ages, we performed a unilateral lesion in the 125-day-old rat SON. Ultrastructural analysis of axon profiles in the NL of the 125-day-old rat demonstrated an absence of axonal sprouting following injury. We previously demonstrated that ciliary neurotrophic factor (CNTF) promotes process outgrowth from injured magnocellular neuron axons in vitro. Thus, we hypothesized that the lack of axonal sprouting in the 125-day-old rat SON may be due to a reduction in CNTF or the CNTF receptor components. To this point, we found that as the rat ages there is significantly less CNTF receptor alpha (CNTFRα) protein in the uninjured, 125-day-old rat compared to the uninjured, 35-day-old rat. We also observed that protein levels of CNTF and the CNTF receptor components were increased in the SON and NL following injury in the 35-day-old rat, but there was no difference in the protein levels in the 125-day-old rat. Altogether, the results presented herein demonstrate that the plasticity within the SON is highly dependent on the age of the rat, and that a decrease in CNTFRα protein levels in the 125-day-old rat may contribute to the loss of axonal sprouting following axotomy.


Subject(s)
Aging/metabolism , Axons/metabolism , Ciliary Neurotrophic Factor Receptor alpha Subunit/metabolism , Supraoptic Nucleus/metabolism , Animals , Axons/chemistry , Axotomy/methods , Ciliary Neurotrophic Factor Receptor alpha Subunit/analysis , Male , Neural Pathways/chemistry , Neural Pathways/metabolism , Rats , Rats, Sprague-Dawley , Supraoptic Nucleus/chemistry
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