Stress peptides sensitize fear circuitry to promote passive coping.

Survival relies on optimizing behavioral responses through experience. Animals often react to acute stress by switching to passive behavioral responses when coping with environmental challenge. Despite recent advances in dissecting mammalian circuitry for Pavlovian fear, the neuronal basis underlying this form of non-Pavlovian anxiety-related behavioral plasticity remains poorly understood. Here, we report that aversive experience recruits the posterior paraventricular thalamus (PVT) and corticotropin-releasing hormone (CRH) and sensitizes a Pavlovian fear circuit to promote passive responding. Site-specific lesions and optogenetic manipulations reveal that PVT-to-central amygdala (CE) projections activate anxiogenic neuronal populations in the CE that release local CRH in response to acute stress. CRH potentiates basolateral (BLA)-CE connectivity and antagonizes inhibitory gating of CE output, a mechanism linked to Pavlovian fear, to facilitate the switch from active to passive behavior. Thus, PVT-amygdala fear circuitry uses inhibitory gating in the CE as a shared dynamic motif, but relies on different cellular mechanisms (postsynaptic long-term potentiation vs. presynaptic facilitation), to multiplex active/passive response bias in Pavlovian and non-Pavlovian behavioral plasticity. These results establish a framework promoting stress-induced passive responding, which might contribute to passive emotional coping seen in human fear- and anxiety-related disorders.

Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats.

Cortical demyelination is a common finding in patients with chronic multiple sclerosis (MS) and contributes to disease progression and overall disability. The exact pathomechanism that leads to cortical lesions is not clear. Research is limited by the fact that standard animal models of multiple sclerosis do not commonly affect the cortex, or if they do in some variants, the cortical demyelination is rather sparse and already remyelinated within a few days. In an attempt to overcome these limitations we implanted a tissue-compatible catheter into the cortex of Dark Agouti rats. After 14days the rats were immunized with 5µg myelin oligodendrocyte glycoprotein (MOG) in incomplete Freund's Adjuvant, which did not cause any clinical signs but animals developed a stable anti-MOG antibody titer. Then the animals received an injection of proinflammatory cytokines through the catheter. This led to a demyelination of cortical and subcortical areas starting from day 1 in a cone-like pattern spreading from the catheter area towards the subarachnoid space. On day 3 cortical demyelination already expanded to the contralateral hemisphere and reached its peak between days 9-15 after cytokine injection with a widespread demyelination of cortical and subcortical areas of both hemispheres. Clinically the animals showed only discrete signs of fatigue and recovered completely after day 15. Even on day 30 we still were able to detect demyelination in subpial and intracortical areas along with areas of partial and complete remyelination. Loss of cortical myelin was accompanied with marked microglia activation. A second injection of cytokines through the catheter on day 30 led to a second demyelination phase with the same symptoms, but again no detectable motor dysfunction. Suffering of the animals appeared minor compared to standard Experimental Autoimmune Encephalomyelitis and therefore, even long-term observation and repeated demyelination phases seem ethically acceptable.

Repetitive long-term hyperbaric oxygen treatment (HBOT) administered after experimental traumatic brain injury in rats induces significant remyelination and a recovery of sensorimotor function.

Cells in the central nervous system rely almost exclusively on aerobic metabolism. Oxygen deprivation, such as injury-associated ischemia, results in detrimental apoptotic and necrotic cell loss. There is evidence that repetitive hyperbaric oxygen therapy (HBOT) improves outcomes in traumatic brain-injured patients. However, there are no experimental studies investigating the mechanism of repetitive long-term HBOT treatment-associated protective effects. We have therefore analysed the effect of long-term repetitive HBOT treatment on brain trauma-associated cerebral modulations using the lateral fluid percussion model for rats. Trauma-associated neurological impairment regressed significantly in the group of HBO-treated animals within three weeks post trauma. Evaluation of somatosensory-evoked potentials indicated a possible remyelination of neurons in the injured hemisphere following HBOT. This presumption was confirmed by a pronounced increase in myelin basic protein isoforms, PLP expression as well as an increase in myelin following three weeks of repetitive HBO treatment. Our results indicate that protective long-term HBOT effects following brain injury is mediated by a pronounced remyelination in the ipsilateral injured cortex as substantiated by the associated recovery of sensorimotor function.