Neuronal substrates underlying stress resilience and susceptibility in rats

Febbraro, Fabia; Svenningsen, Katrine; Tran, Thao Phuong; Wiborg, Ove

doi:10.1371/journal.pone.0179434

Cited by 28 publications

(26 citation statements)

References 70 publications

(76 reference statements)

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“…The detectable elevation in CCO activity of the MHb was consistent with observations reported by Shumake et al (2003) in genetically helpless rats. These results are also in agreement with those reported by Febbraro et al (2017) , who showed that the expression of c-fos was significantly increased in the MHb of CUMS-exposed rats. Altogether, these results suggest that increased metabolism of the MHb may be associated with depression.…”

Section: Discussionsupporting

confidence: 93%

Medial Habenula-Interpeduncular Nucleus Circuit Contributes to Anhedonia-Like Behavior in a Rat Model of Depression

Sun

Cai

et al. 2018

Front. Behav. Neurosci.

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The habenula is a nuclear complex composed of the lateral habenula (LHb) and medial habenula (MHb), two distinct structures. Much progress has been made to emphasize the role of the LHb in the pathogenesis of depression. In contrast, relatively less research has focused on the MHb. However, in recent years, the role of the MHb has begun to gain increasing attention. The MHb connects to the interpeduncular nucleus (IPN) both morphologically and functionally. The MHb-IPN pathway plays an important role in regulating higher brain functions, including cognition, reward, and decision making. It indicates a role of the MHb in the pathogenesis of depression. Thus, we investigated the role of the MHb-IPN pathway in depression. MHb metabolic activity was increased in the chronic unpredictable mild stress (CUMS)-exposed rat model of depression. MHb lesions in the CUMS-exposed rats reversed anhedonia-like behavior, as observed in the sucrose preference test, and significantly downregulated the elevated metabolic activity of the IPN. Substance P (SP)-containing neurons of the MHb were found to innervate the IPN and to be the main source of SP in the IPN. SP content of IPN tissue of the CUMS-exposed rats was increased and MHb lesions reversed this change. In the in vitro experiment, firing rate recordings showed that SP perfusion increased the activity of IPN neurons. Our results suggest that hyperactivity of the MHb-IPN circuit is involved in the anhedonia-like behavior of depression, and that SP mediates the effect of the MHb on IPN neurons.

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Section: Discussionsupporting

confidence: 93%

Medial Habenula-Interpeduncular Nucleus Circuit Contributes to Anhedonia-Like Behavior in a Rat Model of Depression

Sun

Cai

et al. 2018

Front. Behav. Neurosci.

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“…Krishnan and colleagues also found a strong variance in a large cohort of mice submitted to social defeat stress, with a remarkable difference between resilient and prone animals toward stress (Krishnan et al 2007). Febbraro and colleagues recently showed a similar difference in response in rats after chronic mild stress (Febbraro et al 2017).…”

Section: Harmine Is Unable To Reverse Rsd -Induced Anxiety and Depresmentioning

confidence: 92%

Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats

et al. 2020

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Introduction Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. Aim The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. Material and methods Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [ 11 C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. Results RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. Discussion Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.

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“…2009; Febbraro et al . 2017), and found no significant effects of fasting (see also Timofeeva & Richard, 1997; Diano et al . 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we also tested neuronal activation in vivo by c-Fos expression, a traditional tool to measure responses both to acute and continuous stressing (e.g. Murphy et al 2009;Febbraro et al 2017), and found no significant effects of fasting (see also Timofeeva & Richard, 1997;Diano et al 2003). The temporal resolution of c-Fos staining, however, might miss a key stress response that other tests optimized for detection of prolonged neuronal activation (e.g.…”

Section: Intrinsic Mechanisms Of Integrationmentioning

confidence: 97%

Integration of energy homeostasis and stress by parvocellular neurons in rat hypothalamic paraventricular nucleus

Melnick

Krishtal

Colmers

2020

The Journal of Physiology

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Key points Central regulation of energy homeostasis and stress are believed to be reciprocally regulated, i.e. excessive food intake suppresses, while prolonged hunger exacerbates, stress responses in vivo. This relationship may be mediated by neuroendocrine parvocellular corticotropin‐releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus that receive both stress‐ and feeding‐related input. We find that hunger strongly and selectively potentiates, while re‐feeding suppresses, a cellular analogue of a stress response induced by acute glucopenia in CRH neurons in rat hypothalamic slices. Neuronal activation in response to glucopenia was mediated synaptically, via the relative enhancement of glutamate over GABA input. These results illustrate how acute stress responses may be initiated in vivo and show that it is reciprocally integrated with energy balance via local hypothalamic mechanisms acting at the level of CRH neurons and their afferent terminals. Abstract Increased food intake is a common response to help cope with stress, implying the existence of a previously postulated but imperfectly understood, inverse relationship between the regulation of feeding and stress. We have identified components of the neural circuitry that can integrate these homeostatic responses. Prior fasting (∼24 h) potentiates, and re‐feeding suppresses, excitatory responses to acute glucopenia in about half of the corticotropin releasing hormone (CRH)‐expressing, putatively neurosecretory, stress‐related neurons in the paraventricular nucleus of the hypothalamus studied. Glucoprivation stress ex vivo resulted from a preferential relative increase in excitatory (glutamatergic) over inhibitory (GABAergic) inputs. Putative preautonomic cells were less sensitive to fasting, and showed a predominant inhibition to acute glucopenia. We conclude that hunger may sensitize hypothalamic stress responses by acting via local mechanisms, at the level of CRH neurons and their presynaptic inputs. Those mechanisms involve neither presynaptic ATP‐sensitive potassium channels nor postsynaptic ATP levels.

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Neuronal substrates underlying stress resilience and susceptibility in rats

Cited by 28 publications

References 70 publications

Medial Habenula-Interpeduncular Nucleus Circuit Contributes to Anhedonia-Like Behavior in a Rat Model of Depression

Medial Habenula-Interpeduncular Nucleus Circuit Contributes to Anhedonia-Like Behavior in a Rat Model of Depression

Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats

Integration of energy homeostasis and stress by parvocellular neurons in rat hypothalamic paraventricular nucleus

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