Noradrenergic stimulation of α1 adrenoceptors in the medial prefrontal cortex mediates acute stress-induced facilitation of seizures in mice.

Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α1 adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α1 adrenoceptors.

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion.

Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.

A spatiotemporal increase of neuronal activity accompanies the motivational effect of wheel running in mice.

Spatiotemporal patterns of neuronal activity underlying the motivational effect of rotating running wheels (RWs) in rodents remain largely undetermined. Here, we investigated changes of neuronal activity among brain regions associated with motivation across different intensities of motivation for RWs in mice. Daily exposure to RWs gradually increased rotation number, then became stable after approximately 3 weeks. Immunohistochemical analyses revealed that the number of c-Fos (a neuronal activity marker)-positive cells increased in the medial prefrontal cortex (mPFC), core and shell of the nucleus accumbens (NAc), dorsal striatum (Str), and lateral septum (LS) at day 1, day 9, and days 20-24, in a time-dependent manner. Additionally, despite exposure to locked RWs for over 7 days after establishing stable rotation with 3-week RW access, increased c-Fos expression was still observed in most of these brain areas. Furthermore, daily overnight RW access developed stable rotation by day 6, with high and low rotation numbers at the start and end of the overnight session, respectively. The number of c-Fos-positive cells at the start of RW rotation was significantly higher than at the end of RW rotation in most brain regions. Furthermore, after establishing stable rotation, the number of c-Fos-positive cells increased in the mPFC and shell of the NAc of mice that only observed RWs. These findings suggest that the subareas of the mPFC and NAc may be critically involved in the motivational effects of RW rotations.