A Systems Neuroscience Approach to Migraine

Migraine is an extremely common but poorly understood nervous system disorder. We conceptualize migraine as a disorder of sensory network gain and plasticity, and we propose that this framing makes it amenable to the tools of current systems neuroscience

Resolving the neural circuits of anxiety

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIH Director’s New Innovator Award DP2-DK-102256-01)National Institute of Mental Health (U.S.) (NIH) R01-MH102441-01)JPB Foundatio

Modulation of Emotional Faces Processing and Its Implication for Depression and Anxiety

Non

Comparison Of Affective Analgesia And Conditioned Place Preference Following Cholinergic Activation Of

Activation of the dopaminergic mesolimbic reward circuitry that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia, AA). VTA dopamine neurons are activated via cholinergic inputs, and we have observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail-shocks (vocalization afterdischarges = VAD). VADs are a validated rodent model of pain affect. In addition, the capacity of carbachol to support reinforcement appears to be regionally dependent within VTA. Ikemoto and Wise (2002) reported that carbachol was self-administered in the posterior VTA (pVTA), but not the anterior VTA (aVTA). We have previously reported that carbachol preferentially increased the threshold current intensity for eliciting VADs in aVTA and pVTA, but not midVTA. This carbachol-induced AA is mediated by muscarinic receptors within the pVTA and by both muscarinic and nicotinic receptors within the aVTA. Using the conditioned place preference paradigm (CPP), the present study evaluated the muscarinic versus nicotinic involvement in intra-VTA carbachol-induced CPP learning by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into the VTA prior to carbachol treatment. The present study indicates that unilateral carbachol (4 µg/0.25 µl) supports the CPP learning in aVTA and pVTA, but not midVTA. Additionally, both atropine (60 µg/0.25 µl) and mecamylamine (45 µg/0.25 µl) reliably prevented the development of carbachol-induced CPP in the aVTA and pVTA. Thus, this study is the first to directly compare the extent of overlap between cholinergically mediated reward and affective analgesia within different VTA regions. The results are discussed in terms of anatomical and physiological properties of the VTA, with emphasis of cholinergically activated mesolimbic and mesocortical systems. Finally, based on two of the most prominent hypotheses regarding the role of DA in general, a framework is provided for understanding the role of DA in pain, analgesia, and reward in the context of DA function. Grant R01 NS045720 from the National Institute of Neurological Disorders and Stroke supported this research

Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults

Among younger adults, the ability to willfully regulate negative affect, enabling effective responses to stressful experiences, engages regions of prefrontal cortex (PFC) and the amygdala. Because regions of PFC and the amygdala are known to influence the hypothalamic-pituitary-adrenal axis, here we test whether PFC and amygdala responses during emotion regulation predict the diurnal pattern of salivary cortisol secretion. We also test whether PFC and amygdala regions are engaged during emotion regulation in older (62- to 64-year-old) rather than younger individuals. We measured brain activity using functional magnetic resonance imaging as participants regulated (increased or decreased) their affective responses or attended to negative picture stimuli. We also collected saliva samples for 1 week at home for cortisol assay. Consistent with previous work in younger samples, increasing negative affect resulted in ventral lateral, dorsolateral, and dorsomedial regions of PFC and amygdala activation. In contrast to previous work, decreasing negative affect did not produce the predicted robust pattern of higher PFC and lower amygdala activation. Individuals demonstrating the predicted effect (decrease s attend in the amygdala), however, exhibited higher signal in ventromedial prefrontal cortex (VMPFC) for the same contrast. Furthermore, participants displaying higher VMPFC and lower amygdala signal when decreasing compared with the attention control condition evidenced steeper, more normative declines in cortisol over the course of the day. Individual differences yielded the predicted link between brain function while reducing negative affect in the laboratory and diurnal regulation of endocrine activity in the home environment

Amygdala PACAP as a mediator of the emotional components of pain

Chronic pain alters sensory responses and carries a strong emotional component. Persistent pain can heighten pain experiences, resulting in hyperalgesia and allodynia. Further, patients suffering from chronic pain are more prone to experience a range of affective disorders including depression, sleep dysregulation, panic disorders, anxiety abnormalities and stress-related disorders including post-traumatic stress disorder (PTSD). Hence while pain serves a protective function to prevent additional physiological harm by driving behavioral and cognitive responses, chronic or persistent pain can lead to maladaptive nociceptive responses and exacerbate psychopathologies. Among brain regions, the amygdala is centrally situated to integrate the many descending and ascending signals to modulate the sensory and emotional components of pain. The amygdala is well studied for its role in fear and stress-related behavioral processes. The central nucleus of the amygdala (CeA), and in particular the lateral capsular subdivision of the CeA (CeLC), receives prominent ascending pain neurotransmission via the spino- parabrachioamygdaloid tract. In this pathway, peripheral nociceptive signals carried via primary sensory Aδ- and C-fibers terminate in the dorsal horn where second order neurons send projections via the spino-parabrachial pathway to the lateral parabrachial nucleus (LPBn). Thus, the LPBn collects cutaneous (mechanical and thermal), deep (muscular and articular) and visceral nociceptive signals and relays the information in a highly organized manner principally to the CeLC for nociceptive processing. In pain, the CeA and the LPBn-CeLC projections have been shown to undergo plasticity in the forms of enhanced synaptic transmission and alterations in neurotransmitter and receptor expression. Accordingly, the neurocircuit intersections in the CeA can modulate the sensory and emotional responses to pain. Yet despite these associations, the mediators and mechanisms underlying the emotional consequences of pain are poorly understood. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neural and endocrine pleiotropic peptide important in the development and homeostatic regulation of many physiological systems. Recently, the expression of PACAP and its cognate PAC1 receptor has been shown to be upregulated in specific limbic regions by chronic stress. PACAP infusions into several limbic regions is anxiogenic, and altered blood PACAP levels and PAC1 receptor polymorphism have been associated with PTSD and other stress-related disorders. Here, we establish that CeLC PACAP originates from the LPBn as part of the spino-parabrachoamygdaloid pathway. Chronic pain enhanced PACAP expression along LPBn-CeLC projections, indicating it may be a component of pain- related plasticity. CeA PACAP signaling was sufficient to induce nociceptive hypersensitivity and anxiety-like behaviors. In a chronic neuropathic pain model, CeA PACAP signaling was found to contribute to heightened anxiety-like behaviors and nociceptive responses. Further, we characterized one prominent intracellular signaling mechanism through which CeA PACAP signaling influences these behaviors. In these experiments we provide evidence that CeA PACAP signaling plays an important role in the emotional components of pain and that alterations in CeA PACAP signaling are part of pain-related plasticity. This work establishes novel molecular mechanisms that underlie the emotional component of pain and may contribute to the development of chronic pain and associated affective disorders

Modulation of SF1 neuron activity coordinately regulates both feeding behaviour and associated emotional states

Feeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH) regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1) neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans

The Amygdala and Anxiety

The amygdala has a central role in anxiety responses to stressful and arousing situations. Pharmacological and lesion studies of the basolateral, central, and medial subdivisions of the amygdala have shown that their activation induces anxiogenic effects, while their inactivation produces anxiolytic effects. Many neurotransmitters and stress mediators acting at these amygdalar nuclei can modulate the behavioral expression of anxiety. These mediators may be released from different brain regions in response to different types of stressors. The amygdala is in close relationship with several brain regions within the brain circuitry that orchestrates the expression of anxiety. Recent developments in optogenetics have begun to unveil details on how these areas interact

The missing link in early emotional processing

Initial evaluation structures (IESs) currently proposed as the earliest detectors of affective stimuli (e.g., amygdala, orbitofrontal cortex, or insula) are high-order structures (a) whose response latency cannot account for the first visual cortex emotion-related response (~80 ms), and (b) lack the necessary infrastructure to locally analyze the visual features that define emotional stimuli. Several thalamic structures accomplish both criteria. The lateral geniculate nucleus (LGN), a first-order thalamic nucleus that actively processes visual information, with the complement of the thalamic reticular nucleus (TRN) are proposed as core IESs. This LGN–TRN tandem could be supported by the pulvinar, a second-order thalamic structure, and by other extrathalamic nuclei. The visual thalamus, scarcely explored in affective neurosciences, seems crucial in early emotional evaluation.This research was supported by the Ministerio de Ciencia e Innovación (MICINN) (Grant no. PGC2018-093570- B-I00) and the Comunidad de Madrid (Grant no. HUM19-HUM5705)