Ciliary neurotrophic factor signaling in the rat orbitofrontal cortex ameliorates stress-induced deficits in reversal learning

Girotti, Milena; Silva, Jeri D.; George, Christina; Morilak, David A.

doi:10.1016/j.neuropharm.2019.107791

Cited by 8 publications

(5 citation statements)

References 77 publications

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“…Activation of MeA neurons triggers dopamine release in the nucleus accumbens, suggesting that CNTF in the MeA regulates the function of reward circuitry that is closely linked to anhedonia. Others have found that chronic intermittent cold stress reduces CNTF in rat orbitofrontal cortex of both sexes, which leads to reversal learning deficit ( Girotti et al, 2019 ). The apparent discrepancy with our finding that stress increases CNTF in females could be due to the paradigm of stress, brain areas, and/or endpoint measurements.…”

Section: Discussionmentioning

confidence: 99%

“…Stress responses help to maintain homeostasis by regulating multiple neural circuits and effector molecules in the brain ( Deussing and Chen, 2018 ). A recent study shows that chronic intermittent cold stress reduces CNTF in the rat orbitofrontal cortex, which leads to reversal learning deficit ( Girotti et al, 2019 ), suggesting a contribution of CNTF in stress response. We previously identified a striking sex-specific effect of CNTF on immobility in the forced swim in mice.…”

Section: Introductionmentioning

confidence: 99%

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Female-specific role of ciliary neurotrophic factor in the medial amygdala in promoting stress responses

Jia

Gill

Lovins

et al. 2022

Neurobiology of Stress

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Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF−/− littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF−/− mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Female-specific role of ciliary neurotrophic factor in the medial amygdala in promoting stress responses

Jia

Gill

Lovins

et al. 2022

Neurobiology of Stress

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“…Thus, we selected 30’ as our tissue collection time. Western blots were performed as described previously [ 30 ]. Membranes were incubated in anti-rabbit or mouse secondary antibody (1:5,000 Cell Signaling) detected using ECL Prime (GE Healthcare, Little Chalfont, UK).…”

Section: Methodsmentioning

confidence: 99%

“…As the different vehicles (0.5% DMSO in saline, 70% DMSO in saline, or saline alone) did not differ and had no effect on behavior, these groups were combined into a single vehicle group to minimize animal usage. Both LY294002 and PD98059 at the selected doses effectively inhibit phosphorylation of Akt and Erk in vivo, respectively [ 30 , 32 ]. Based on preliminary western blot experiments showing phosphorylation of TrkB at Y515 occurred 30 mins post FE, we administered the inhibitors immediately after the end of the 32-minute extinction session so drug administration would precede induction of phosphorylation of Y515.…”

Section: Methodsmentioning

confidence: 99%

“…Cognitive flexibility is the ability to modify previously established associations, thoughts, or responses based on changes in the environment [ 30 ]. Cognitive flexibility deficits represent a symptom dimension shared across several psychiatric disorders, are associated with increased symptom severity in PTSD [ 5 ], and are a risk factor for developing MDD [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats

Paredes

Knippenberg

Morilak

2021

Neuropsychopharmacol.

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Current pharmacotherapies for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are ineffective for many patients, and often do not restore cognitive dysfunction associated with these disorders. Behavioral therapies, such as exposure therapy, can be effective for treatment-resistant patients. The mechanisms underlying exposure therapy are not well-understood. Fear extinction as an intervention after chronic stress can model the beneficial effects of exposure therapy in rats. Extinction requires neuronal activity and protein synthesis in the infralimbic (IL) cortex for its beneficial effects. We hypothesized that extinction requires Brain-Derived Neurotrophic Factor (BDNF) activity in the IL cortex to reverse stress-induced cognitive flexibility impairments. Extinction learning reversed set-shifting deficits induced by Chronic Unpredictable Stress (CUS), tested 24 h after extinction. Blocking BDNF signaling in the IL cortex during extinction by local administration of a neutralizing antibody prevented the beneficial effects of extinction on set shifting after stress. Extinction induced activation of the BDNF TrkB receptor, and signaling pathways associated with BDNF (Akt and Erk). Administration of exogenous BDNF into IL cortex in the absence of extinction was sufficient to reverse the effects of stress on set shifting. The effects of extinction were prevented by blocking either Erk or Akt signaling in the IL cortex, whereas the effects of exogenous BDNF were dependent on Erk, but not Akt, signaling. Our observations suggest that BDNF-Erk signaling induced by extinction underlies plastic changes that can reverse or counteract the effects of chronic stress in the IL cortex.

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The combination of autologous mesenchymal stem cell-derived exosomes and neurotrophic factors as an intervention for amyotrophic lateral sclerosis

Ding

Botchway

Zhang

et al. 2022

Annals of Anatomy - Anatomischer Anzeiger

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Ciliary neurotrophic factor signaling in the rat orbitofrontal cortex ameliorates stress-induced deficits in reversal learning

Cited by 8 publications

References 77 publications

Female-specific role of ciliary neurotrophic factor in the medial amygdala in promoting stress responses

Female-specific role of ciliary neurotrophic factor in the medial amygdala in promoting stress responses

Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats

The combination of autologous mesenchymal stem cell-derived exosomes and neurotrophic factors as an intervention for amyotrophic lateral sclerosis

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