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Neuropsychopharmacology : Official... Jan 2022The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (MDD). Although functional and structural PFC... (Review)
Review
The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (MDD). Although functional and structural PFC abnormalities have been reported in both individuals with current MDD as well as those at increased vulnerability to MDD, this information has not translated into better treatment and prevention strategies. Here, we argue that dissecting depressive phenotypes into biologically more tractable dimensions - negative processing biases, anhedonia, despair-like behavior (learned helplessness) - affords unique opportunities for integrating clinical findings with mechanistic evidence emerging from preclinical models relevant to depression, and thereby promises to improve our understanding of MDD. To this end, we review and integrate clinical and preclinical literature pertinent to these core phenotypes, while emphasizing a systems-level approach, treatment effects, and whether specific PFC abnormalities are causes or consequences of MDD. In addition, we discuss several key issues linked to cross-species translation, including functional brain homology across species, the importance of dissecting neural pathways underlying specific functional domains that can be fruitfully probed across species, and the experimental approaches that best ensure translatability. Future directions and clinical implications of this burgeoning literature are discussed.
Topics: Anhedonia; Brain; Depression; Depressive Disorder, Major; Humans; Magnetic Resonance Imaging; Prefrontal Cortex
PubMed: 34341498
DOI: 10.1038/s41386-021-01101-7 -
Molecular Psychiatry Dec 2019Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the... (Review)
Review
Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the precise neural mechanisms underlying the development of depression remain elusive. Although it is impossible to phenocopy every symptom of human depression in rodents, the preclinical field has had great success in modeling some of the core affective and neurovegetative depressive symptoms, including social withdrawal, anhedonia, and weight loss. Adaptations in select cell populations may underlie these individual depressive symptoms and new tools have expanded our ability to monitor and manipulate specific cell types. This review outlines some of the most recent preclinical discoveries on the molecular and neurophysiological mechanisms in reward circuitry that underlie the expression of behavioral constructs relevant to depressive symptoms.
Topics: Anhedonia; Animals; Depression; Depressive Disorder, Major; Disease Models, Animal; Humans; Motivation; Reward; Social Behavior; Weight Loss
PubMed: 30967681
DOI: 10.1038/s41380-019-0415-3 -
Clinical Psychopharmacology and... Aug 2023Anhedonia is a core symptom of depression and of several psychiatric disorders. Anhedonia has however expanded from its original definition to encompass a spectrum of... (Review)
Review
Anhedonia is a core symptom of depression and of several psychiatric disorders. Anhedonia has however expanded from its original definition to encompass a spectrum of reward processing deficits that received much interest in the last decades. It is a relevant risk factor for possible suicidal behaviors, and that it may operate as an independent risk factor for suicidality apart from the episode severity. Anhedonia has also been linked to inflammation with a possible reciprocal deleterious effect on depression. Its neurophysiological bases mainly include alterations in striatal and prefrontal areas, with dopamine being the most involved neurotransmitter. Anhedonia is thought to have a significant genetic component and polygenic risk scores are a possible tool for predicting an individual's risk for developing anhedonia. Traditional antidepressants, such as selective serotonin reuptake inhibitors, showed a limited benefit on anhedonia, also considering their potential pro-anhedonic effect in some subjects. Other treatments may be more effective in treating anhedonia, such as agomelatine, vortioxetine, ketamine and transcranial magnetic stimulation. Psychotherapy is also widely supported, with cognitive-behavioral therapy and behavioral activation both showing benefit. In conclusion, a large body of evidence suggests that anhedonia is, at least partially, independent from depression, therefore it needs careful assessment and targeted treatment.
PubMed: 37424409
DOI: 10.9758/cpn.23.1086 -
Neuron May 2023Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric...
Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.
Topics: Mice; Animals; Dopamine; Propofol; Dopamine Plasma Membrane Transport Proteins; Molecular Docking Simulation; Receptors, Dopamine D1; Nucleus Accumbens; Anhedonia; Mice, Inbred C57BL
PubMed: 36917979
DOI: 10.1016/j.neuron.2023.02.017 -
Neuroscience and Biobehavioral Reviews Jul 2019Depression is linked to deficits in cognitive control and a host of other cognitive impairments arise as a consequence of these deficits. Despite of their important role... (Review)
Review
Depression is linked to deficits in cognitive control and a host of other cognitive impairments arise as a consequence of these deficits. Despite of their important role in depression, there are no mechanistic models of cognitive control deficits in depression. In this paper we propose how these deficits can emerge from the interaction between motivational and cognitive processes. We review depression-related impairments in key components of motivation along with new cognitive neuroscience models that focus on the role of motivation in the decision-making about cognitive control allocation. Based on this review we propose a unifying framework which connects motivational and cognitive control deficits in depression. This framework is rooted in computational models of cognitive control and offers a mechanistic understanding of cognitive control deficits in depression.
Topics: Anhedonia; Cognitive Dysfunction; Decision Making; Depressive Disorder; Executive Function; Humans; Models, Biological; Motivation; Reward
PubMed: 31047891
DOI: 10.1016/j.neubiorev.2019.04.011 -
Nature Communications Aug 2023Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these...
Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3→DA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3 → DA glutamatergic transmission and DA neural excitability. VGluT3 → DA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3 → DA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3 → DA → D2/D1 pathway in establishing and modulating chronic pain and CAB.
Topics: Humans; Ventral Tegmental Area; Chronic Pain; Dorsal Raphe Nucleus; Neuralgia; Anhedonia; Dopaminergic Neurons; Glutamic Acid
PubMed: 37612268
DOI: 10.1038/s41467-023-40860-3 -
The American Journal of Psychiatry Jul 2022Anhedonia-the loss of pleasure or lack of reactivity to pleasurable stimuli-remains a formidable treatment challenge across neuropsychiatric disorders. In major... (Review)
Review
Anhedonia-the loss of pleasure or lack of reactivity to pleasurable stimuli-remains a formidable treatment challenge across neuropsychiatric disorders. In major depressive disorder, anhedonia has been linked to poor disease course, worse response to psychological, pharmacological, and neurostimulation treatments, and increased suicide risk. Moreover, although some neural abnormalities linked to anhedonia normalize after successful treatment, several persist-for example, blunted activation of the ventral striatum to reward-related cues and reduced functional connectivity involving the ventral striatum. Critically, some of these abnormalities have also been identified in unaffected, never-depressed children of parents with major depressive disorder and have been found to prospectively predict the first onset of major depression. Thus, neural abnormalities linked to anhedonia may be promising targets for prevention. Despite increased appreciation of the clinical importance of anhedonia and its underlying neural mechanisms, important gaps remain. In this overview, the author first summarizes the extant knowledge about the pathophysiology of anhedonia, which may provide a road map toward novel treatment and prevention strategies, and then highlights several priorities to facilitate clinically meaningful breakthroughs. These include a need for 1) appropriately controlled clinical trials, especially those embracing an experimental therapeutics approach to probe target engagement; 2) novel preclinical models relevant to anhedonia, with stronger translational value; and 3) clinical scales that incorporate neuroscientific advances in our understanding of anhedonia. The author concludes by highlighting important future directions, emphasizing the need for an integrated, collaborative, cross-species, and multilevel approach to tackling anhedonic phenotypes.
Topics: Anhedonia; Depressive Disorder, Major; Humans; Magnetic Resonance Imaging; Reward; Ventral Striatum
PubMed: 35775159
DOI: 10.1176/appi.ajp.20220423 -
Nutrients Jul 2020Obesity is characterized by massive adipose tissue accumulation and is associated with psychiatric disorders and cognitive impairment in human and animal models....
Obesity is characterized by massive adipose tissue accumulation and is associated with psychiatric disorders and cognitive impairment in human and animal models. However, it is unclear whether high-fat diet (HFD)-induced obesity presents a risk of psychiatric disorders and cognitive impairment. To examine this question, we conducted systematic behavioral analyses in C57BL/6J mice (male, 8-week-old) fed an HFD for 7 weeks. C57BL/6J mice fed an HFD showed significantly increased body weight, hyperlocomotion in the open-field test (OFT) and Y-maze test (YMZT), and impaired sucrose preference in the sucrose consumption test, compared to mice fed a normal diet. Neither body weight nor body weight gain was associated with any of the behavioral traits we examined. Working memory, as assessed by the YMZT, and anxiety-like behavior, as assessed by the elevated plus maze test (EPMT), were significantly correlated with mice fed an HFD, although these behavioral traits did not affect the entire group. These results suggest that HFD-induced obesity does not induce neuropsychiatric symptoms in C57BL/6J mice. Rather, HFD improved working memory in C57BL/6J mice with less anxiety, indicating that an HFD might be beneficial under limited conditions. Correlation analysis of individual traits is a useful tool to determine those conditions.
Topics: Anhedonia; Animals; Anxiety; Behavior, Animal; Cognition; Diet, High-Fat; Elevated Plus Maze Test; Male; Maze Learning; Memory, Short-Term; Mice, Inbred C57BL; Motor Activity; Open Field Test; Weight Gain
PubMed: 32659954
DOI: 10.3390/nu12072036 -
Immunity Feb 2021Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major...
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.
Topics: Anhedonia; Animals; Animals, Genetically Modified; Behavior, Animal; Cells, Cultured; Corpus Striatum; Depression; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Macrophage Activation; Mice; Microglia; Neurogenic Inflammation; Neurons; Prostaglandins
PubMed: 33476547
DOI: 10.1016/j.immuni.2020.12.016