Activation of the subthalamic nucleus suppressed by high frequency stimulation: A c-Fos immunohistochemical study.

Deep brain stimulation applied at high frequency (HFS) to the subthalamic nucleus (STN) is used to ameliorate the symptoms of Parkinson's disease. The mechanism by which this is achieved remains controversial. In particular, it is uncertain whether HFS has a suppressive or excitatory action locally within the STN. Brief exposure of rats to ether anesthesia evokes pathological burst firing and associated expression of the immediate early gene c-Fos in STN neurons. We used this ether model of STN activation to test the effect of a range of HFS parameters on c-Fos expression evoked by the anesthetic. The elevated baseline of c-Fos expression afforded the possibility of detecting further excitatory, or suppressive effects of STN HFS. Four HFS protocols were examined; 130, 200 and 260 Hz with 60 µs, and 130 Hz with 90 µs pulse width (HFS intensity:150-300 µA). All HFS protocols were applied for 20 min while the animals were exposed to ether. Ether-evoked expression of c-Fos immunoreactivity was suppressed by HFS at 200 and 260 Hz with a pulse width of 60 µs, and by 130 Hz when the pulse width was increased to 90 µs. HFS at 130 Hz with the 60 µs pulse width had no significant effect and HFS alone caused negligible c-Fos expression in the STN. These findings suggest that HFS of the STN causes significant suppression of evoked neuronal activity. It remains to be determined whether this locally suppressive property of HFS is associated with the efficacy of STN deep brain stimulation to relieve the symptoms of Parkinson's disease.

Reinforcement determines the timing dependence of corticostriatal synaptic plasticity in vivo.

Plasticity at synapses between the cortex and striatum is considered critical for learning novel actions. However, investigations of spike-timing-dependent plasticity (STDP) at these synapses have been performed largely in brain slice preparations, without consideration of physiological reinforcement signals. This has led to conflicting findings, and hampered the ability to relate neural plasticity to behavior. Using intracellular striatal recordings in intact rats, we show here that pairing presynaptic and postsynaptic activity induces robust Hebbian bidirectional plasticity, dependent on dopamine and adenosine signaling. Such plasticity, however, requires the arrival of a reward-conditioned sensory reinforcement signal within 2 s of the STDP pairing, thus revealing a timing-dependent eligibility trace on which reinforcement operates. These observations are validated with both computational modeling and behavioral testing. Our results indicate that Hebbian corticostriatal plasticity can be induced by classical reinforcement learning mechanisms, and might be central to the acquisition of novel actions.Spike timing dependent plasticity (STDP) has been studied extensively in slices but whether such pairings can induce plasticity in vivo is not known. Here the authors report an experimental paradigm that achieves bidirectional corticostriatal STDP in vivo through modulation by behaviourally relevant reinforcement signals, mediated by dopamine and adenosine signaling.