Chronic stress affects the number of GABAergic neurons in the orbitofrontal cortex of rats

Varga, Zsófia; Csabai, Dávid; Miseta, Attila; Wiborg, Ove; Czéh, Boldizsár

doi:10.1016/j.bbr.2016.08.030

Cited by 44 publications

(46 citation statements)

References 58 publications

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“…These include cortisol and related HPA axis feedback loops (cortisol secreted during a stress response) that increase blood sugar, suppress the immune system, and aid in metabolism to facilitate responses to perceived challenge, uncertainty or threat Sustained (chronic) stress levels in the body can lead to high blood pressure and muscle damage [ 93 ]. Evidence from animal and human studies furthermore suggests that chronic stress might lead to a variety of effects on the brain, including cell destruction, changes in proportions of cell types, and decreased plasticity [ 94 ] in regions including the hippocampus [ 95 – 97 ], medial prefrontal cortex [ 98 , 99 ] and orbitofrontal cortex [ 100 ]. Thus, one can argue for these priors from an evolutionary perspective, under which prior preferences for prolonged and chronic states of stress would be low (i.e.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic and extrinsic motivators of attachment under active inference

Cittern¹,

Nolte²,

Friston³

et al. 2018

PLoS ONE

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This paper addresses the formation of infant attachment types within the context of active inference: a holistic account of action, perception and learning in the brain. We show how the organised forms of attachment (secure, avoidant and ambivalent) might arise in (Bayesian) infants. Specifically, we show that these distinct forms of attachment emerge from a minimisation of free energy—over interoceptive states relating to internal stress levels—when seeking proximity to caregivers who have a varying impact on these interoceptive states. In line with empirical findings in disrupted patterns of affective communication, we then demonstrate how exteroceptive cues (in the form of caregiver-mediated AMBIANCE affective communication errors, ACE) can result in disorganised forms of attachment in infants of caregivers who consistently increase stress when the infant seeks proximity, but can have an organising (towards ambivalence) effect in infants of inconsistent caregivers. In particular, we differentiate disorganised attachment from avoidance in terms of the high epistemic value of proximity seeking behaviours (resulting from the caregiver’s misleading exteroceptive cues) that preclude the emergence of coherent and organised behavioural policies. Our work, the first to formulate infant attachment in terms of active inference, makes a new testable prediction with regards to the types of affective communication errors that engender ambivalent attachment.

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Section: Resultsmentioning

confidence: 99%

Intrinsic and extrinsic motivators of attachment under active inference

Cittern¹,

Nolte²,

Friston³

et al. 2018

PLoS ONE

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“…We have been studying the effect of stress on GABAergic neurons for many years and we have repeatedly documented that stress can disrupt the functional and morphological integrity of GABAergic neurons in the hippocampus (Czéh et al, 2005 , 2016 ; Hu et al, 2010 , 2011 ; Holm et al, 2011 ; Nieto-Gonzalez et al, 2015 ; Csabai et al, 2017 ) and in the orbitofrontal cortex (Varga et al, 2017 ). It appears that the effect of stress on GABAergic neurons is region specific.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats

Czéh

Vardya

Varga³

et al. 2018

Front. Cell. Neurosci.

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Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II–III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABAB receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.

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“…The unpredictable CMS animal model of depression investigated here is considered one of the most realistic models of depression with the demonstrated face, predictive, etiological and construct validity [ 39 , 56 , 57 ]. This model has been investigated using neuronal tracing techniques, stereology and immunohistochemistry, and has demonstrated significant microstructural alteration in brain regions, such as hippocampus [ 25 , 58 – 60 ], prefrontal cortex [ 61 , 62 ], amygdala [ 25 , 63 , 64 ] and caudate putamen [ 63 ]. However, microstructural alterations in cortical regions except for prefrontal cortex have not previously been subjected to investigation.…”

Section: Discussionmentioning

confidence: 99%

Differential microstructural alterations in rat cerebral cortex in a model of chronic mild stress depression

et al. 2018

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Chronic mild stress leads to depression in many cases and is linked to several debilitating diseases including mental disorders. Recently, neuronal tracing techniques, stereology, and immunohistochemistry have revealed persistent and significant microstructural alterations in the hippocampus, hypothalamus, prefrontal cortex, and amygdala, which form an interconnected system known as the stress circuit. Most studies have focused only on this circuit, however, some studies indicate that manipulation of sensory and motor systems may impact genesis and therapy of mood disorders and therefore these areas should not be neglected in the study of brain microstructure alterations in response to stress and depression. For this reason, we explore the microstructural alterations in different cortical regions in a chronic mild stress model of depression. The study employs ex-vivo diffusion MRI (d-MRI) to assess cortical microstructure in stressed (anhedonic and resilient) and control animals. MRI is followed by immunohistochemistry to substantiate the d-MRI findings. We find significantly lower extracellular diffusivity in auditory cortex (AC) of stress groups and a significantly higher fractional anisotropy in the resilient group. Neurite density was not found to be significantly higher in any cortical ROIs in the stress group compared to control, although axonal density is higher in the stress groups. We also report significant thinning of motor cortex (MC) in both stress groups. This is in agreement with recent clinical and preclinical studies on depression and similar disorders where significant microstructural and metabolic alterations were found in AC and MC. Our findings provide further evidence that the AC and MC are sensitive towards stress exposure and may extend our understanding of the microstructural effects of stress beyond the stress circuit of the brain. Progress in this field may provide new avenues of research to help in diagnosis and treatment intervention for depression and related disorders.

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Chronic stress affects the number of GABAergic neurons in the orbitofrontal cortex of rats

Cited by 44 publications

References 58 publications

Intrinsic and extrinsic motivators of attachment under active inference

Intrinsic and extrinsic motivators of attachment under active inference

Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats

Differential microstructural alterations in rat cerebral cortex in a model of chronic mild stress depression

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