Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs.
Focused ultrasound heating of ex vivo bovine kidney and liver was monitored using magnetic resonance imaging (MRI) to investigate the quantitative relationship between time-dependent temperature elevations and altered contrast in MR images due to thermal coagulation. Proton resonance frequency shift MR thermometry was performed during heating at 10 sec intervals (single-slice fast spoiled GRASS [ Thermal coagulation therapy (local heat treatment of tumors using heat sources such as focused ultrasound, radiofrequency, microwave, or laser energy) is currently receiving increased attention due to the potential of magnetic resonance imaging (MRI) to provide guidance and monitoring. For guidance to be feasible, MRI must provide the capability to assess, in near real-time and three spatial dimensions, when cells in a given target volume are sufficiently heated to cause thermal coagulation and necrosis, and when heating of surrounding normal tissues becomes excessive. Ideally, this assessment would be quantitative to enable automatic feedback control of the heat source, which requires detailed understanding of the changes in MR image contrast both during and after tissue heating.It has long been recognized that multiple MR parameters are sensitive to changes in both temperature and tissue microstructure that occur with thermal coagulation from heating (1-3). The changes due to each of these effects are not necessarily additive; for example, the T1 relaxation time of liver is observed to increase with temperature, and to decrease with thermal coagulation (4). Furthermore, the appearance of altered contrast in MR images due to changes in temperature does not directly correlate with regions of cell death, particularly if the temperature change is small (5). The cumulative effect of both temperature and thermal coagulation on contrast in standard clinical MR images is likely to be highly complex, therefore, providing a suboptimal strategy for image guidance. A better strategy is first to exploit specific MR parameters that are sensitive to temperature and insensitive to thermal coagulation, to perform MR thermometry during heat treatment. At present, MRI that exploits the proton resonance frequency (PRF) shift with temperature is receiving the most attention for this purpose (6), and the insensitivity of the PRF shift during thermal coagulation has recently been confirmed ex vivo (7). Second, images heavily weighted by MR parameters that are sensitive to thermal coagulation [eg, T1, T2, or potentially magnetization transfer (8)] can be used to visualize the zone of thermal coagulation post heating with optimal contrast. Guidance is thus reduced to establishing the relationship between temperature as a function of heating time and cell viability. The relationship can be investigated directly, or effectively in two parts: a) understanding the relationship between MR thermometry and the changes in contrast observed in post-heating images, and b) understanding how the changes in post-heating images relate to the actual zone of...
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