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a Numerous labeled neurons are found in the parasubthalamic nucleus (PSTN) ipsilateral to the AmCe injection. The most ventrally located, larger labeled neurons probably correspond to the magnocellular nucleus of the lateral hypothalamus (Paxinos and Watson 1998). Medial is to the left, the border of the PSTN to the subthalamic nucleus (STN) is indicated by a dashed line. ped cerebral peduncle. b Following an injection centered in AmBl heavily labeled neurons are found in the peripeduncular nucleus (PP) and a moderate number in the posterior intralaminar thalamic nucleus (PIL). More ventrally, large strongly labeled neurons are found in the substantia nigra pars lateralis (SNl) and a moderate number in the substantia nigra pars compacta (SNc). SNr substantia nigra pars reticulata. Scale bars = 200 lm
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A recently revealed important function of the amygdala (Am) is that it acts as the brain's "lighthouse", which constantly monitors the environment for stimuli which signal a threat to the organism. The data from patients with extensive lesions of the striate cortex indicate that "unseen" fearful and fear-conditioned faces elicit increased Am respon...
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... labeling of the further structures of the brain stem Following injections in AmCe strong retrograde labeling is observed in the ipsilateral parasubthalamic nucleus (PSTN) that surrounds the medial corner of the sub- thalamic nucleus (Fig. 5a). Substantial labeling in the PSTN was seen also following caudolateral injections that reached the piriform cortex, while following medial and anterior injections only occasional PSTN neurons were ...
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... Anatomical studies indicate that the pontine tegmentum and NTS could activate the LC; moreover, noradrenergic terminals from the LC innervate the amygdala (Robertson et al., 2013;Uematsu et al., 2017;Usunoff et al., 2006). These findings corroborate a linear contribution of the NTS-LC-amygdala NA pathway in aversive learning. ...
... The PBG projects to the ipsilateral pulvinar, and bilaterally to the dorsal lateral geniculate nucleus (dLGN), central amygdala, and SC (Diamond et al., 1992;Usunoff et al., 2007;Shang et al., 2015Shang et al., , 2018Whyland et al., 2020;Sokhadze et al., 2022). Retrograde tracing studies have revealed that PBG neurons can branch to innervate several different contralateral targets, while ipsilateral projections arise from separate populations of PBG neurons (Sefton and Martin, 1984;Usunoff et al., 2006Usunoff et al., , 2007. Moreover, several studies have noted that PBG neurons that project to the contralateral SC are larger than those that project to the ipsilateral SC, and additionally that the PBG forms anterior/posterior subdivisions corresponding to these contralateral or ipsilateral projections, respectively (Watanabe and Kawana, 1979;Jen et al., 1984;Künzle and Schnyder, 1984;Baizer et al., 1991;Jiang et al., 1996;Deichler et al., 2020). ...
The superior colliculus (SC) is a critical hub for the generation of visually-evoked orienting and defensive behaviors. Among the SC’s myriad downstream targets is the parabigeminal nucleus (PBG), the mammalian homolog of the nucleus isthmi, which has been implicated in motion processing and the production of defensive behaviors. The inputs to the PBG are thought to arise exclusively from the SC but little is known regarding the precise synaptic relationships linking the SC to the PBG. In the current study, we use optogenetics as well as viral tracing and electron microscopy in mice to better characterize the anatomical and functional properties of the SC-PBG circuit, as well as the morphological and ultrastructural characteristics of neurons residing in the PBG. We characterized GABAergic SC-PBG projections (that do not contain parvalbumin) and glutamatergic SC-PBG projections (which include neurons that contain parvalbumin). These two terminal populations were found to converge on different morphological populations of PBG neurons and elicit opposing postsynaptic effects. Additionally, we identified a population of non-tectal GABAergic terminals in the PBG that partially arise from neurons in the surrounding tegmentum, as well as several organizing principles that divide the nucleus into anatomically distinct regions and preserve a coarse retinotopy inherited from its SC-derived inputs. These studies provide an essential first step toward understanding how PBG circuits contribute to the initiation of behavior in response to visual signals.
... The amygdala receives dense presynaptic inputs from the posterior thalamus (Craig et al., 1994(Craig et al., , 2000Gauriau and Bernard, 2004;Price, 2002) and the parabrachial nucleus (Usunoff et al., 2006), relay centers that process innate and learned signals of several sensory modalities (e.g., auditory [Yasui et al., 1992], somatosensory [Nakamura and Morrison, 2008], and gustatory [Jarvie et al., 2021]). Subregions of these areas, the parvocellular subparafascicular nucleus (SPFp; also referred to as the posterior thalamus or posterior intralaminar nucleus in the thalamus) (D'Hanis et al., 2007;Dobolyi et al., 2005;Kruger et al., 1988) and external lateral parabrachial nucleus (PBel), highly express calcitonin gene-related peptide (CGRP), a neuropeptide associated with aversion and nociception (Palmiter, 2018;Russell et al., 2014;Russo, 2015;Shinohara et al., 2017;Yu et al., 2009). ...
Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory modalities to multiple brain areas, such as the midbrain and hypothalamus, for immediate avoidance. Yet little is known about whether and how multi-sensory innate threat cues are integrated and conveyed from each sensory modality to the amygdala, a critical brain area for threat perception and learning. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafascicular nucleus in the thalamus and external lateral parabrachial nucleus in the brainstem respond to multi-sensory threat cues from various sensory modalities and relay negative valence to the lateral and central amygdala, respectively. Both CGRP populations and their amygdala projections are required for multi-sensory threat perception and aversive memory formation. The identification of unified innate threat pathways may provide insights into developing therapeutic candidates for innate fear-related disorders.
... Many of these projections are reciprocated by target structures, such that the PSTN receives dense inputs from the CeA (a unique feature that differentiates the PSTN from other hypothalamic areas), medial IPAC, sublenticular SI, lateral area of the anterior BNST (oval and rhomboid nuclei in particular), lateral and medial PBN, and, to a smaller extent, NTS (Barbier et al., 2017;Chometton et al., 2016;Dong et al., 2000Dong et al., , 2001Dong and Swanson, 2003;Shammah-Lagnado et al., 2001;Usunoff et al., 2006;Zseli et al., 2016). The PSTN also receives afferents from the AI (particularly from the dorsal and posterior areas), infralimbic cortex, paraventricular nucleus of the hypothalamus, lateral habenula, amygdalopiriform transition area, ventral tegmental area, ventral PAG, DRN, and pre-locus coeruleus (Barbier et al., 2020;Chometton et al., 2016;Muzerelle et al., 2016;Santiago and Shammah-Lagnado, 2005;Shin et al., 2011). ...
The parasubthalamic nucleus (PSTN), a small nucleus located on the lateral edge of the posterior hypothalamus, has emerged in recent years as a highly interconnected node within the network of brain regions sensing and regulating autonomic function and homeostatic needs. Furthermore, the strong integration of the PSTN with extended amygdala circuits makes it ideally positioned to serve as an interface between interoception and emotions. While PSTN neurons are mostly glutamatergic, some of them also express neuropeptides that have been associated with stress-related affective and motivational dysfunction, including substance P, corticotropin-releasing factor, and pituitary adenylate-cyclase activating polypeptide. PSTN neurons respond to food ingestion and anorectic signals, as well as to arousing and distressing stimuli. Functional manipulation of defined pathways demonstrated that the PSTN serves as a central hub in multiple physiologically relevant networks and is notably implicated in appetite suppression, conditioned taste aversion, place avoidance, impulsive action, and fear-induced thermoregulation. We also discuss the putative role of the PSTN in interoceptive dysfunction and negative urgency. This review aims to synthesize the burgeoning preclinical literature dedicated to the PSTN and to stimulate interest in further investigating its influence on physiology and behavior.
... Such neurons do not project directly to the PAG but they do to the parabigeminal nucleus (PBGN) and the LPTN (Figures 1F, 2E, 3B). LPTN projects to LA (Doron and LeDoux, 2000) while PBGN projects to CeA (Usunoff et al., 2006;Shang et al., 2015) and dlPAG (Meller and Dennis, 1986;Klop et al., 2006). Activity within the SuC-LTPN-LA pathway has been shown to trigger freezing (Shang et al., 2015(Shang et al., , 2018Wei et al., 2015) whereas, PBGN has been shown to initiate a behavioral pattern of escape-and-freeze responses (Shang et al., 2018). ...
Brain-wide neural circuits enable bi- and quadrupeds to express adaptive locomotor behaviors in a context- and state-dependent manner, e.g., in response to threats or rewards. These behaviors include dynamic transitions between initiation, maintenance and termination of locomotion. Advances within the last decade have revealed an intricate coordination of these individual locomotion phases by complex interaction of multiple brain circuits. This review provides an overview of the neural basis of state-dependent modulation of locomotion initiation, maintenance and termination, with a focus on insights from circuit-centered studies in rodents. The reviewed evidence indicates that a brain-wide network involving excitatory circuit elements connecting cortex, midbrain and medullary areas appears to be the common substrate for the initiation of locomotion across different higher-order states. Specific network elements within motor cortex and the mesencephalic locomotor region drive the initial postural adjustment and the initiation of locomotion. Microcircuits of the basal ganglia, by implementing action-selection computations, trigger goal-directed locomotion. The initiation of locomotion is regulated by neuromodulatory circuits residing in the basal forebrain, the hypothalamus, and medullary regions such as locus coeruleus. The maintenance of locomotion requires the interaction of an even larger neuronal network involving motor, sensory and associative cortical elements, as well as defined circuits within the superior colliculus, the cerebellum, the periaqueductal gray, the mesencephalic locomotor region and the medullary reticular formation. Finally, locomotor arrest as an important component of defensive emotional states, such as acute anxiety, is mediated via a network of survival circuits involving hypothalamus, amygdala, periaqueductal gray and medullary premotor centers. By moving beyond the organizational principle of functional brain regions, this review promotes a circuit-centered perspective of locomotor regulation by higher-order states, and emphasizes the importance of individual network elements such as cell types and projection pathways. The realization that dysfunction within smaller, identifiable circuit elements can affect the larger network function supports more mechanistic and targeted therapeutic intervention in the treatment of motor network disorders.
... The fraction of crossing connections from brainstem nuclei in humans has not been reported in detail. However, studies in primates, cats, rodents, and other mammals universally show that reciprocal connections (afferent and efferent) of important subcortical structures, including the amygdala, SN, basal forebrain nuclei, and LC are almost exclusively ipsilateral (Fig. 3A) [32][33][34][35][36][37][38][39][40][41][42][43][44]. ...
... If the initial ␣-synuclein pathology in brain-first PD arises unilaterally in the amygdala or the LC, the ipsilateral SN would be involved soon thereafter, since the SN has strong ipsilateral connections to both the LC and amygdala [33,34,38,39,86,87]. The dopaminergic neurons in the SN ipsilateral to the origin site would therefore get a head start and degenerate earlier than the contralateral SN. ...
A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α-synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.
... In the contralateral SC, the terminal fibers were restricted to the medial part of the SC (mSC), throughout the rostral-caudal axis, consistent with the retrograde results ( Fig. 7d-g). In addition, in cases that we failed to target the PBG, but our tracer deposits were located in the medial-adjacent peri-parabigeminal area (n = 4) (also known as nucleus sagulum in the mouse, and microcellular tegmental nucleus in the rat 30 ), we observed intense bilateral fiber labeling in the intermediate and deep In the ipsilateral pPBG, cells filled by either fluorophore are segregated in space indicating that this division projects topographically to the SC (green and red arrowheads in (a)); terminal fibers filled only with the tracer injected in the medial SC (CTB-555) are seen in the ipsilateral aPBG (white arrowheads in (a)). In the contralateral aPBG, retrograde transport is restricted to fluorescent CTB injected in the medial SC (b), indicating that this PBG division projects only to this part of the contralateral SC. ...
... Based on optogenetic manipulations it has been suggested that the PBG generates escape reactions through glutamatergic connections with the CeA 16,17 . While a PBG-CeA projection has been reported in several studies 16,17,30,35 , this interpretation overlooks the tight reciprocal SC-PBG connections www.nature.com/scientificreports/ and the role of the SC in organizing escape reactions. ...
the parabigeminal nucleus (pBG) is the mammalian homologue to the isthmic complex of other vertebrates. optogenetic stimulation of the pBG induces freezing and escape in mice, a result thought to be caused by a pBG projection to the central nucleus of the amygdala. However, the isthmic complex, including the pBG, has been classically considered satellite nuclei of the Superior colliculus (Sc), which upon stimulation of its medial part also triggers fear and avoidance reactions. As the pBG‑Sc connectivity is not well characterized, we investigated whether the topology of the pBG projection to the Sc could be related to the behavioral consequences of pBG stimulation. to that end, we performed immunohistochemistry, in situ hybridization and neural tracer injections in the Sc and pBG in a diurnal rodent, the Octodon degus. We found that all pBG neurons expressed both glutamatergic and cholinergic markers and were distributed in clearly defined anterior (aPBG) and posterior (ppBG) subdivisions. the ppBG is connected reciprocally and topographically to the ipsilateral SC, whereas the aPBG receives afferent axons from the ipsilateral SC and projected exclusively to the contralateral SC. This contralateral projection forms a dense field of terminals that is restricted to the medial SC, in correspondence with the SC representation of the aerial binocular field which, we also found, in O. degus prompted escape reactions upon looming stimulation. therefore, this specialized topography allows binocular interactions in the Sc region controlling responses to aerial predators, suggesting a link between the mechanisms by which the Sc and pBG produce defensive behaviors.
... In humans, electrical stimulation of the amygdala results in an apnea (Dlouhy et al., 2015), suggesting that the amygdala is functionally coupled to the brainstem bCPG. The CeA receives input from cortex, limbic system, hypothalamus, olfactory pathway, substantia nigra, and many brainstem nuclei (Usunoff et al., 2006;Bienkowski and Rinaman, 2013;Gu et al., 2020), and processes information to generate a breathing response to emotional stimuli, mediated at least in part by direct projections to the bCPG. ...
The key driver of breathing rhythm is the preBötzinger Complex (preBötC) whose activity is modulated by various functional inputs, e.g., volitional, physiological, and emotional. While the preBötC is highly interconnected with other regions of the breathing central pattern generator (bCPG) in the brainstem, there is no data about the direct projections to either excitatory and inhibitory preBötC subpopulations from other elements of the bCPG or from suprapontine regions. Using modified rabies tracing, we identified neurons throughout the brain that send monosynaptic projections to identified excitatory and inhibitory preBötC neurons in mice. Within the brainstem, neurons from sites in the bCPG, including the contralateral preBötC, Bötzinger Complex, the nucleus of the solitary tract (NTS), parafacial region (pF
L
/pF
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), and parabrachial nuclei (PB), send direct projections to both excitatory and inhibitory preBötC neurons. Suprapontine inputs to the excitatory and inhibitory preBötC neurons include the superior colliculus, red nucleus, amygdala, hypothalamus, and cortex; these projections represent potential direct pathways for volitional, emotional, and physiological control of breathing.
... Anatomical studies indicate that the amygdala is innervated by noradrenergic neurons in the LC, pontine tegmentum and NTS, any of which could drive adrenergic receptor activity in LA/B or regulate the central amygdala (CeA; Fig. 1) 92,93 . However, recent studies using optogenetic manipulations demonstrated the importance of LC projections to the LA/B in aversive learning and behavior 84,94,95 . ...
Emotional learning and memory are functionally and dysfunctionally regulated by the neuromodulatory state of the brain. While the role of excitatory and inhibitory neural circuits mediating emotional learning and its control have been the focus of much research, we are only now beginning to understand the more diffuse role of neuromodulation in these processes. Recent experimental studies of the acetylcholine, noradrenaline and dopamine systems in fear learning and extinction of fear responding provide surprising answers to key questions in neuromodulation. One area of research has revealed how modular organization, coupled with context-dependent coding modes, allows for flexible brain-wide or targeted neuromodulation. Other work has shown how these neuromodulators act in downstream targets to enhance signal-to-noise ratios and gain, as well as to bind distributed circuits through neuronal oscillations. These studies elucidate how different neuromodulatory systems regulate aversive emotional processing and reveal fundamental principles of neuromodulatory function. In this Review, Likhtik and Johansen discuss how modern neuroscience techniques applied to the study of emotional learning reveal new principles for how neuromodulatory systems regulate distributed brain circuits and flexibly adjust behaviour.
... These neurons seem to have properties similar to the respiratory chemoreceptors identified in the rostral medulla oblongata [84]. The A5 region has connections with the NTS, RVLM, caudal ventrolateral medulla (CVLM), caudal pressor area and the retrotrapezoid nucleus in the medulla oblongata; with the mPB, lPB and KF in the pons; and with the PeF, the PVN and the amygdala in the hypothalamus [85][86][87][88][89][90]. These connections with regions of the central nervous system involved in cardiorespiratory regulation are indicative for a role of the A5 region in the control of both sympathetic activity and cardiorespiratory function [81,91,92]. ...
Stimulation of discrete sites throughout the hypothalamus elicits autonomic and somatic responses. This chapter will stand out the cardiorespiratory changes evoked from stimulation of specific areas within the caudal hypothalamus: the perifornical area and the dorsomedial nucleus. The stimulation of these regions, known as the hypothalamic defense area (HDA), produces a pattern of visceral and somatic changes characteristic of the defense reaction, which includes tachypnoea, tachycardia and a pressor response. A close review of the literature demonstrates that the changes observed during this defensive behavioral response are partially mediated by the interactions with pontine regions. These include the parabrachial complex, located in the dorsolateral pons, and the A5 region, located in the ventrolateral pons. Specific glutamatergic stimulation of cell bodies located within the parabrachial complex and A5 region evokes cardiorespiratory responses similar to those observe during stimulation of the HDA. This functional interaction suggests a possible role of glutamate pontine receptors in the modulation of the HDA response. This chapter describes the most important evidences confirming the implication of the dorso and ventrolateral pons in the control of cardiorespiratory autonomic responses evoked from the perifornical and dorsomedial hypothalamus and the role of glutamate in this interaction
