Authors: Xuaner Xiang, Fei Wang, Chao Chen...

Understanding neural circuits involved in anesthesia is crucial for improving its safety and efficacy. Hypothalamic orexin neurons (LHA ), projecting broadly, are essential in regulating arousal and pain. However, the precise targets remain unclear. Here we investigated the orexin projections to the substantia innominata (SI). Combining optogenetics, fiber photometry, and EEG/EMG allowed us to manipulate orexin activities, while simultaneously recording local ligand release and global cortical activities during anesthesia. Brain slice electrophysiology revealed the synaptic connections in the SI, while RNAscope was employed to examine the distribution of orexin receptors and downstream neuronal types. Presynaptic vesicles were identified in the orexin terminals in the SI, where 49.16% of cells expressed OX2R and 6.8% expressed OX1R. Orexin release in the SI was reversibly suppressed by isoflurane. Optogenetic activation of the LHA →SI circuit significantly increased orexin release and promoted arousal from various anesthesia stages, including reanimation during 0.75% isoflurane (p < 0.0001), prolongation of 3% isoflurane induction (p = 0.0033), and acceleration of emergence from 2% isoflurane (p < 0.0001). Furthermore, activating this circuit induced analgesia to both thermal (p = 0.0074) and inflammatory (p = 0.0127) pain. Patch-clamp recordings revealed that optogenetic activation of orexin terminals in the SI elicited excitatory postsynaptic currents, which were blocked by the OX2R antagonist. SI contains more GABAergic (28.17%) and glutamatergic (11.96%) neurons than cholinergic neurons (4.13%), all of which expressed OX2R. Thus, LHA neurons innervate SI neurons to regulate both arousal and pain predominantly through OX2R.

PubMed: 39554139
DOI: 10.1101/2024.10.29.620973

Authors: Yuting Cui, Xiaodan Huang, Pengcheng Huang...

The lateral habenula (LHb) is implicated in emotional processing, especially depression. Recent studies indicate that the basal forebrain (BF) transmits reward or aversive signals to the LHb. However, the contribution of the BF-LHb circuit to the pathophysiology of depression still needs to be determined. Here, we find that the excitatory projection to the LHb from the substantia innominata (SI), a BF subregion, is activated by aversive stimuli and inhibited by reward stimuli. Furthermore, chronic activation of the SI-LHb circuit is sufficient to induce depressive-like behaviors, whereas inhibition of the circuit alleviates chronic stress-induced depressive-like phenotype. We also find that reward consumption buffers depressive-like behaviors induced by chronic activation of the SI-LHb circuit. In summary, we systematically define the function and mechanism of the SI-LHb circuit in modulating depressive-like behaviors, thus providing important insights to better decipher LHb processing in the pathophysiology of depression.

PubMed: 35857453
DOI: 10.1126/sciadv.abn0193

Authors: R H Perry, J M Candy, E K Perry...

The substantia innominata was investigated in the adult human brain with particular reference to the cholinergic nature of the nucleus of Meynert. Based on histochemical observations of acetylcholinesterase activity and biochemical estimations of choline acetyltransferase the relations of the Meynert nucleus to adjacent structures in the substantia innominata region were identified precisely. A new dissection procedure is described which permits combined histochemical and histological examination of anatomically complex regions of the human brain, such as the substantia innominata, to be carried out in conjunction with accurate tissue dissection for neurochemical analysis. Using this technique, various acetylcholinesterase-positive and choline acetyltransferase-containing structures are apparent in coronal sections removed from the rostrocaudal length of the substantia innominata. These include, in addition to the prominently stained, putative cholinergic neurons, acetylcholinesterase-positive tracts which contain putative cholinergic projections to the neocortex, and 'islands' of acetylcholinesterase-positive neuropil which presumably reflect a collateral or intrinsic cholinergic innervation in the area. This anatomical complexity of cholinergic structures in the substantia innominata suggests that neurochemical analysis should be conducted on microdissected as opposed to macrodissected tissue samples. Neuropathologically, the present report provides a further basis for optimising quantification of putative cholinergic perikarya. Continued systematic analysis of the nucleus of Meynert at the morphological and biochemical level should thus establish the role of this nucleus in normal brain function and in disease.

Topics: Acetylcholinesterase; Adult; Aged; Basal Ganglia; Choline O-Acetyltransferase; Cholinergic Fibers; Cytoplasm; Histocytochemistry; Humans; Middle Aged; Neurons; Substantia Innominata; Supraoptic Nucleus

PubMed: 6746407
DOI: No ID Found

Authors: Lindsay J Agostinelli, Joel C Geerling, Thomas E Scammell...

The basal forebrain (BF) contains at least three distinct populations of neurons (cholinergic, glutamatergic, and GABA-ergic) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Much attention has focused on the BF's ascending projections to cortex, but less is known about descending projections to subcortical regions. Given the neurochemical and anatomical heterogeneity of the BF, we used conditional anterograde tracing to map the patterns of subcortical projections from multiple BF regions and neurochemical cell types using mice that express Cre recombinase only in cholinergic, glutamatergic, or GABAergic neurons. We confirmed that different BF regions innervate distinct subcortical targets, with more subcortical projections arising from neurons in the caudal and lateral BF (substantia innominata and magnocellular preoptic area). Additionally, glutamatergic and GABAergic BF neurons have distinct patterns of descending projections, while cholinergic descending projections are sparse. Considering the intensity of glutamatergic and GABAergic descending projections, the BF likely acts through subcortical targets to promote arousal, motivation, and other behaviors.

Topics: Animals; Basal Forebrain; Brain Mapping; Choline O-Acetyltransferase; Dynorphins; Female; Glutamic Acid; Luminescent Proteins; Mice; Mice, Transgenic; Nerve Net; Neural Pathways; Neurons; Transduction, Genetic; Vesicular Glutamate Transport Protein 2; Vesicular Inhibitory Amino Acid Transport Proteins; Red Fluorescent Protein

PubMed: 30612231
DOI: 10.1007/s00429-018-01820-6

Authors: Fan Mei, Chen Zhao, Shangjin Li...

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.

Topics: Animals; Prefrontal Cortex; Cholinergic Neurons; Acetylcholine; Mice; Male; Mice, Knockout; Recognition, Psychology; Basal Nucleus of Meynert; Mice, Inbred C57BL; Pyramidal Cells; Hippocampus; Receptors, Nerve Growth Factor

PubMed: 39187496
DOI: 10.1038/s41467-024-51707-w

Authors: Zhenggang Zhu, Qingqing Ma, Lu Miao...

Although aggressive behaviors are universal and essential for survival, "uncontrollable" and abnormal aggressive behaviors in animals or humans may have severe adverse consequences or social costs. Neural circuits regulating specific forms of aggression under defined conditions have been described, but how brain circuits govern a general aggressive response remains unknown. Here, we found that posterior substantia innominata (pSI) neurons responded to several aggression-provoking cues with the graded activity of differential dynamics, predicting the aggressive state and the topography of aggression in mice. Activation of pSI neurons projecting to the periaqueductal gray (PAG) increased aggressive arousal and robustly initiated/promoted all the types of aggressive behavior examined in an activity-level-dependent manner. Inactivation of the pSI circuit largely blocked diverse aggressive behaviors but not mating. By encoding a general aggressive response, the pSI-PAG circuit universally drives multiple aggressive behaviors and may provide a potential target for alleviating human pathological aggression.

Topics: Aggression; Animals; Behavior, Animal; Male; Mesencephalon; Mice; Neural Pathways; Neurons; Substantia Innominata

PubMed: 33740417
DOI: 10.1016/j.neuron.2021.03.002

Authors: Sean J Colloby, Greg J Elder, Riham Rabee...

OBJECTIVES

Several cholinergic nuclei, and in particular the nucleus basalis of Meynert, are localised to the substantia innominata in the basal forebrain. These nuclei provide major cholinergic innervation to the cerebral cortex and hippocampus, and have an essential role in cognitive function. The aim of this study was to investigate volumetric grey matter (GM) changes in the substantia innominata from structural T1 images in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy older participants using voxel-based morphometry.

METHODS

Participants (41 DLB, 47 AD and 39 controls) underwent 3 T T1 magnetic resonance imaging and cognitive assessments. Voxel-based morphometry analysis used SPM8 with a substantia innominata brain mask to define the subspace for voxel GM analyses. Group differences, and selected behavioural and clinical correlates, were assessed.

RESULTS

Compared with that in controls, bilateral GM loss in the substantia innominata was apparent in both AD and DLB. Relative to controls, significant bilateral GM loss in the substantia innominata was observed in DLB and AD. In DLB, significant associations were also observed between substantia innominata GM volume loss, and the levels of cognitive impairment and severity of cognitive fluctuations.

CONCLUSIONS

Relative to that controls, atrophy of the substantia innominata was apparent in DLB and AD, and is associated with specific clinical manifestations in DLB. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Case-Control Studies; Female; Gray Matter; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Substantia Innominata

PubMed: 27197956
DOI: 10.1002/gps.4500

Authors: Brian E Powers, Christy M Kelley, Ramon Velazquez...

The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12-17months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.

Topics: Animals; Attention; Basal Forebrain; Cell Count; Cell Size; Choline; Cholinergic Neurons; Dietary Supplements; Disease Models, Animal; Down Syndrome; Female; Male; Maternal Nutritional Physiological Phenomena; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mothers; Organ Size; Pregnancy; Random Allocation

PubMed: 27840230
DOI: 10.1016/j.neuroscience.2016.11.001

Review

Authors: Timm B Poeppl, Berthold Langguth, Rainer Rupprecht...

Sexual preference determines mate choice for reproduction and hence guarantees conservation of species in mammals. Despite this fundamental role in human behavior, current knowledge on its target-specific neurofunctional substrate is based on lesion studies and therefore limited. We used meta-analytic remodeling of neuroimaging data from 364 human subjects with diverse sexual interests during sexual stimulation to quantify neural regions associated with sexual preference manipulations. We found that sexual preference is encoded by four phylogenetically old, subcortical brain structures. More specifically, sexual preference is controlled by the anterior and preoptic area of the hypothalamus, the anterior and mediodorsal thalamus, the septal area, and the perirhinal parahippocampus including the dentate gyrus. In contrast, sexual non-preference is regulated by the substantia innominata. We anticipate the identification of a core neural circuit for sexual preferences to be a starting point for further sophisticated investigations into the neural principles of sexual behavior and particularly of its aberrations.

Topics: Animals; Brain; Humans; Neurons; Sexual Behavior; Sexual Behavior, Animal

PubMed: 27339689
DOI: 10.1016/j.neubiorev.2016.06.025

Authors: J M Candy, R H Perry, J E Thompson...

A dense peptidergic innervation has been demonstrated in the substantia innominata region in postmortem specimens of human brain using immunocytochemical techniques. A peptidergic innervation of the nucleus of Meynert - the prominent nucleus of this area containing the cholinergic cell bodies which innervate the cerebral cortex - has been demonstrated by immunostaining with antisera against the following eight neuropeptides: somatostatin, substance P, cholecystokinin octapeptide, vasoactive intestinal polypeptide, met-enkephalin, ACTH, alpha-MSH and oxytocin. Other immunocytochemical features of the substantia innominata region include a dense band of peptide immunoreactivity beneath the medial aspect of the anterior commissure and islands of somatostatin and substance P terminal immunoreactivity in the rostral part of the substantia innominata. Somatostatin immunostained cell bodies have been located in a discrete area of the bed nucleus of the stria terminalis and in the rostral portion of the substantia innominata, nucleus accumbens and the ventral part of the putamen. The dense band of peptide immunoreactivity beneath the medial aspect of the anterior commissure consists of ribbon-like processes stained with antisera against somatostatin, substance P, cholecystokinin octapeptide, vasoactive intestinal polypeptide and met-enkephalin. Less intense immunostaining of ribbon-like elements is also present in the globus pallidus. The presence of a peptidergic innervation to the nucleus of Meynert suggests a possible important modulatory role in cortical cholinergic function.

Topics: Adrenocorticotropic Hormone; Aged; Brain Chemistry; Cholecystokinin; Enkephalin, Methionine; Humans; Immunochemistry; Melanocyte-Stimulating Hormones; Middle Aged; Nerve Tissue Proteins; Oxytocin; Somatostatin; Substance P; Vasoactive Intestinal Peptide; Vasopressins

PubMed: 2416723
DOI: No ID Found