From Traumatic Childhood to Cocaine Abuse: The Critical Function of the Immune System

Iacono, Luisa Lo; Catale, Clarissa; Martini, Alessandro; Valzania, Alessandro; Viscomi, Maria Teresa; Chiurchiù, Valerio; Guatteo, Ezia; Bussone, Silvia; Perrone, Fabiana; Sabato, Paola Di; Aricò, Eleonora; D’Argenio, Alberto; Troisi, Alfonso; Mercuri, Nicola Biagio; Maccarrone, Mauro; Puglisi-Allegra, Stefano; Casella, Pietro; Carola, Valeria

doi:10.1016/j.biopsych.2018.05.022

Cited by 60 publications

(48 citation statements)

References 58 publications

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“…D2 auto-receptor pathways show plasticity and are dynamically regulated by reward circuits and drugs of abuse (Beckstead et al, 2007;Courtney et al, 2012). Here, we found that the VTA DA neurons from the socially defeated mice lost their inhibitory responses to DA, which is consistent with other results reported that social defeat stress reduces the degree of DA-mediated self-inhibition of VTA DA neurons, and also the amplitude of DA-induced outward currents in the VTA (Lo Iacono et al, 2018). We speculate that the coupling between the D2 receptor and Kv7 was altered, or that the D2 receptor was downregulated or desensitized, or mechanisms targeted by microglia after social defeat stress (Ford, 2014;Lo Iacono et al, 2018).…”

Section: Discussionsupporting

confidence: 92%

Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area

Wang

et al. 2019

Front. Cell. Neurosci.

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Dopaminergic neurons in the ventral tegmental area (VTA) encode behavioral patterns important in reward and drug addiction as well as in emotional disorders. These functions of dopamine neurons are directly related to the release of dopamine in the targeted regions of the brain which are, thus, controlled by the excitability of dopamine neurons. One mechanism for modulation of dopamine neuronal excitability is mediated by the auto dopamine type 2 (D2) receptors, through activation of a Kir3/GIRK K + channel which inhibits the firing of dopamine neurons. In this study, we provide evidence that Kv7.4, in addition to Kir3.2 channels, contributes to dopamine (DA)-mediated auto-inhibition of DA activity projecting to NAc and to basolateral amygdale (BLA). Furthermore, we demonstrate that D2 receptors enhance Kv7.4 currents through G i/o protein and redoxdependent cellular pathway. Finally, we show this D2 mediated auto-inhibition is blunted in a social defeat mice model of depression, a phenomenon that may contribute to the altered excitability of VTA DA neurons in depressed animals. These results provide a new perspective for understanding the molecular mechanism of the excitability of VTA DA neurons and for potential new strategies against mental disorders involving altered excitability of DA neurons, such as major depression and drug addictions.

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Section: Discussionsupporting

confidence: 92%

Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area

Wang

et al. 2019

Front. Cell. Neurosci.

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“…In adulthood, cell density returned to control levels, but microglia displayed increased soma size and process complexity close to the soma. Interestingly, the microglial cells of stressed mice showed a higher IBA-1 percentage of expression in response to cocaine injection (5 mg/kg) with respect to controls, indicating a possible effect of early social stress on microglial priming [69]. Differently, a paradigm of social instability stress applied during adolescence (isolation and change of cage partner) did not produce effects on counts of microglia in the dentate gyrus (HIP) either early or later after the stress exposure [70].…”

Section: Postnatal Behavioral Stressorsmentioning

confidence: 93%

“…First, many of these studies have focused on one or few target structures for investigation, particularly the HIP. As reviewed by Tan, Yuan, and Tian (2019), microglia show regional heterogeneity in density, morphology, and phenotype, which may underlie differential responsivity to stimuli, including stress and inflammatory conditions [69,169]. This spatial heterogeneity could be important for tuning neuronal/glial functions and neural circuitry, thus contributing to the region-specific effects of ELS on the brain.…”

Section: Perspectivesmentioning

confidence: 99%

“…Recently, our group (2018) demonstrated that periadolescent social stress-induced microglial activation mediated dopaminergic system dysfunctionality and cocaine-induced behavioral alterations. Indeed, these effects were rescued by either minocycline or GW2580 (selective inhibitor of CSF1R) administration during the stress procedure [69].…”

Section: Effects Of Postnatal-stress-induced Microglial Alterations Omentioning

confidence: 99%

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Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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“…The number of branch points (nodes), processes that intersected the radii, was measured as a function of the distance from the cell soma for each radius. 24,32 Data were collected and stored for statistical analysis. Fifteen cells per animal were randomly selected for a total of 90 cells per group (N = 6 mice/group) and included for analysis.…”

Section: Quantitative Analysis Of Microgliamentioning

confidence: 99%

Impairment of DHA synthesis alters the expression of neuronal plasticity markers and the brain inflammatory status in mice

Talamonti

Sasso

et al. 2019

FASEB j.

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Docosahexaenoic acid (DHA) is a ω‐3 fatty acid typically obtained from the diet or endogenously synthesized through the action of elongases (ELOVLs) and desaturases. DHA is a key central nervous system constituent and the precursor of several molecules that regulate the resolution of inflammation. In the present study, we questioned whether the impaired synthesis of DHA affected neural plasticity and inflammatory status in the adult brain. To address this question, we investigated neural and inflammatory markers from mice deficient for ELOVL2 (Elovl2−/−), the key enzyme in DHA synthesis. From our findings, Elovl2−/− mice showed an altered expression of markers involved in synaptic plasticity, learning, and memory formation such as Egr‐1, Arc1, and BDNF specifically in the cerebral cortex, impacting behavioral functions only marginally. In parallel, we also found that DHA‐deficient mice were characterized by an increased expression of pro‐inflammatory molecules, namely TNF, IL‐1β, iNOS, caspase‐1 as well as the activation and morphologic changes of microglia in the absence of any brain injury or disease. Reintroducing DHA in the diet of Elovl2−/− mice reversed such alterations in brain plasticity and inflammation. Hence, impairment of systemic DHA synthesis can modify the brain inflammatory and neural plasticity status, supporting the view that DHA is an essential fatty acid with an important role in keeping inflammation within its physiologic boundary and in shaping neuronal functions in the central nervous system.

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From Traumatic Childhood to Cocaine Abuse: The Critical Function of the Immune System

Abstract: Collectively, our findings demonstrate that sensitization to cocaine in early life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans.

Cited by 60 publications

References 58 publications

Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area

Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Impairment of DHA synthesis alters the expression of neuronal plasticity markers and the brain inflammatory status in mice

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