Background-The neocortex is the most common target of sub-dural electrotherapy and noninvasive brain stimulation modalities including transcranial magnetic stimulation (TMS) and transcranial current simulation (TCS). Specific neuronal elements targeted by cortical stimulation are considered to underlie therapeutic effects, but the exact cell-type(s) affected by these methods remains poorly understood.

Sensory processing is often regarded as a passive process in which a biological sensors like photoand mechanoreceptors transducer physical energy into a neural code. Recent findings, however, suggest that: 1) most sensory processing is active, and largely determined by motor/attentional sampling routines, 2) due to rhythmicity in the motor routine, as well as to its entrainment of ambient rhythms in sensory regions, sensory inflow tends to be rhythmic, and 3) attentional manipulation of rhythms in sensory pathways is instrumental to perceptual selection. These observations outline the essentials of an Active Sensing paradigm, and argue for increased emphasis on the study of sensory processes as specific to the dynamic motor/attentional context in which inputs are acquired.

Despite compelling phenomenological evidence that small electric fields (Ͻ5 mV/mm) can affect brain function, a quantitative and experimentally verified theory is currently lacking. Here we demonstrate a novel mechanism by which the nonlinear properties of single neurons "amplify" the effect of small electric fields: when concurrent to suprathreshold synaptic input, small electric fields can have significant effects on spike timing. For low-frequency fields, our theory predicts a linear dependency of spike timing changes on field strength. For high-frequency fields (relative to the synaptic input), the theory predicts coherent firing, with mean firing phase and coherence each increasing monotonically with field strength. Importantly, in both cases, the effects of fields on spike timing are amplified with decreasing synaptic input slope and increased cell susceptibility (millivolt membrane polarization per field amplitude). We confirmed these predictions experimentally using CA1 hippocampal neurons in vitro exposed to static (direct current) and oscillating (alternating current) uniform electric fields. In addition, we develop a robust method to quantify cell susceptibility using spike timing. Our results provide a precise mechanism for a functional role of endogenous field oscillations (e.g., gamma) in brain function and introduce a framework for considering the effects of environmental fields and design of low-intensity therapeutic neurostimulation technologies.

Androgens have dramatic effects on neuronal structure and function in hippocampus. However, androgen depletion does not always lead to hippocampal impairment. To address this apparent paradox, we evaluated the hippocampus of adult male rats after gonadectomy (Gdx) or sham surgery. Surprisingly, Gdx rats showed increased synaptic transmission and long-term potentiation (LTP) of the mossy fiber (MF) pathway. Gdx rats also exhibited increased excitability and MF sprouting. We then addressed the possible underlying mechanisms, and found that Gdx induced a long-lasting upregulation of MF brain-derived neurotrophic factor (BDNF) immunoreactivity. Antagonism of Trk receptors, which bind neurotrophins such as BDNF, reversed the increase in MF transmission, excitability and LTP in Gdx rats, but there were no effects of Trk antagonism in sham controls. To determine which androgens were responsible, the effects of testosterone metabolites dihydrotestosterone (DHT) and 5α-androstane-3α,17β-diol were examined. Exposure of slices to 50 nM DHT decreased the effects of Gdx on MF transmission but 50 nM 5α-androstane-3α,17β-diol had no effect. Remarkably, there was no effect of DHT in control males. The data suggest that a Trk- and androgen receptor-sensitive form of MF transmission and synaptic plasticity emerges after Gdx. We suggest that androgens may normally be important in area CA3 to prevent hyperexcitability and aberrant axon outgrowth, but limit MF synaptic transmission and some forms of plasticity. The results also suggest a potential explanation for the maintenance of hippocampal-dependent cognitive function after androgen depletion: a reduction in androgens may lead to compensatory upregulation of MF transmission and plasticity.

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