Vascular responses of penetrating vessels during cortical spreading depolarization with ultrasound dynamic ultrafast Doppler imaging.

The dynamic vascular responses during cortical spreading depolarization (CSD) are causally related to pathophysiological consequences in numerous neurovascular conditions, including ischemia, traumatic brain injury, cerebral hemorrhage, and migraine. Monitoring of the hemodynamic responses of cerebral penetrating vessels during CSD is motivated to understand the mechanism of CSD and related neurological disorders. Six SD rats were used, and craniotomy surgery was performed before imaging. CSDs were induced by topical KCl application. Ultrasound dynamic ultrafast Doppler was used to access hemodynamic changes, including cerebral blood volume (CBV) and flow velocity during CSD, and further analyzed those in a single penetrating arteriole or venule. The CSD-induced hemodynamic changes with typical duration and propagation speed were detected by ultrafast Doppler in the cerebral cortex ipsilateral to the induction site. The hemodynamics typically showed triphasic changes, including initial hypoperfusion and prominent hyperperfusion peak, followed by a long-period depression in CBV. Moreover, different hemodynamics between individual penetrating arterioles and venules were proposed by quantification of CBV and flow velocity. The negative correlation between the basal CBV and CSD-induced change was also reported in penetrating vessels. These results indicate specific vascular dynamics of cerebral penetrating vessels and possibly different contributions of penetrating arterioles and venules to the CSD-related pathological vascular consequences. We proposed using ultrasound dynamic ultrafast Doppler imaging to investigate CSD-induced cerebral vascular responses. With this imaging platform, it has the potential to monitor the hemodynamics of cortical penetrating vessels during brain injuries to understand the mechanism of CSD in advance.

NMDA receptors sustain but do not initiate neuronal depolarization in spreading depolarization.

Spreading depolarization (SD) represents a neurological process characterized by a massive, self-sustaining wave of brain cell depolarization. Understanding its mechanism is important for treating ischemic or hemorrhagic stroke and migraine with aura. Many believed that ion fluxes through NMDA receptors (NMDARs) are responsible for neuronal transmembrane currents of SD. However, the explicit role of NMDARs remains ambiguous. This is in part due to the limitation of traditional pharmacological approaches in resolving the contribution of NMDARs in different intercellular and intracellular processes of SD. Here, we applied single-cell blockade and genetic deletion methods to remove functional NMDARs from individual hippocampal CA1 neurons in order to examine the role of NMDARs in the depolarization mechanism without affecting the propagation of SD. We analyzed neuronal membrane potential changes to demonstrate that NMDARs are not required for initiating the depolarization. Consistently, neuronal input resistance (RN) revealed a sharp decline at the start of SD, which was unaffected by blocking NMDARs. Instead, the recovery of both membrane potential and RN during the late phase of SD was facilitated by inhibition of NMDARs, indicating that NMDARs are responsible for sustaining the depolarization. Our results strongly indicate that NMDAR activation is not a determinant of the initiation of depolarization but is important for sustaining transmembrane ion fluxes during SD.

Astrocytic Regulation of Glutamate Transmission in Schizophrenia.

According to the glutamate hypothesis of schizophrenia, the abnormality of glutamate transmission induced by hypofunction of NMDA receptors (NMDARs) is causally associated with the positive and negative symptoms of schizophrenia. However, the underlying mechanisms responsible for the changes in glutamate transmission in schizophrenia are not fully understood. Astrocytes, the major regulatory glia in the brain, modulate not only glutamate metabolism but also glutamate transmission. Here we review the recent progress in understanding the role of astrocytes in schizophrenia. We focus on the astrocytic mechanisms of (i) glutamate synthesis via the glutamate-glutamine cycle, (ii) glutamate clearance by excitatory amino acid transporters (EAATs), (iii) D-serine release to activate NMDARs, and (iv) glutamatergic target engagement biomarkers. Abnormality in these processes is highly correlated with schizophrenia phenotypes. These findings will shed light upon further investigation of pathogenesis as well as improvement of biomarkers and therapies for schizophrenia.

Involvements of stress hormones in the restraint-induced conditioned place preference.

The conditioned place preference (CPP) paradigm is widely used when examining the reinforcing effects of drugs. Some previous studies have shown that an acute stressor, such as restraint could also induce CPP. Although the modulating effects of stress hormones on various forms of learning are well known, the finding that a stressor has a potentially direct role in the reinforcement mechanism is novel. This study focused on the function of stress hormones in restraint-induced CPP in Wistar rats administered agonist or antagonist of 2 critical stress hormones prior to conditioning. Results showed that peripheral applications of corticosterone (CORT, 1, 3, 5, and 10 mg/kg, subcutaneously) failed to induce CPP. Furthermore, a glucocorticoid (GC) antagonist (mifepristone, 10, 40, or 100 mg/kg, sc) failed to block the restraint-induced CPP. Intracerebroventricular injection of a selective corticotropin-releasing factor receptor 1 (CRFR1) antagonist antalarmin (1 µg/5 µl), on the contrary, completely blocked the restraint-induced CPP. We concluded that CRFR1 plays an essential role in the neural mechanism of restraint-induced CPP. Negative feedback of CORT from peripheral sources may not be involved in this phenomenon.