Trk tyrosine kinases are receptors for members of the neurotrophin family and are crucial for growth and survival of specific populations of neurons. Yet, the functions of neurotrophin-Trk signaling in postnatal development as well as maintenance and plasticity of the adult nervous system are less clear. We report here the generation of mice harboring Trk knockin alleles that allow for pharmacological control of Trk kinase activity. Nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkA(F592A) and TrkB(F616A) neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkA(F592A), TrkB(F616A), and TrkC(F167A) signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.

No abstract

Adaptive behavior requires the ability to flexibly control actions. This can occur either proactively to anticipate task requirements, or reactively in response to sudden changes. Here we report neuronal activity in the supplementary motor area (SMA) that is correlated with both forms of behavioral control. Single-unit and multiunit activity and intracranial local field potentials (LFPs) were recorded in macaque monkeys during a stop-signal task, which elicits both proactive and reactive behavioral control. The LFP power in high-(60 -150 Hz) and low-(25-40 Hz) frequency bands was significantly correlated with arm movement reaction time, starting before target onset. Multiunit and single-unit activity also showed a significant regression with reaction time. In addition, LFPs and multiunit and single-unit activity changed their activity level depending on the trial history, mirroring adjustments on the behavioral level. Together, these findings indicate that neuronal activity in the SMA exerts proactive control of arm movements by adjusting the level of motor readiness. On trials when the monkeys successfully canceled arm movements in response to an unforeseen stop signal, the LFP power, particularly in a low (10 -50 Hz) frequency range, increased early enough to be causally related to the inhibition of the arm movement on those trials. This indicated that neuronal activity in the SMA is also involved in response inhibition in reaction to sudden task changes. Our findings indicate, therefore, that SMA plays a role in the proactive control of motor readiness and the reactive inhibition of unwanted movements.

Voluntary control of behavior implies the ability to select what action is performed. The supplementary motor area (SMA) and pre-SMA are widely considered to be of central importance for this ability because of their role in movement initiation and inhibition. To test this hypothesis, we recorded from neurons in SMA and pre-SMA of monkeys performing an arm countermanding task. Temporal analysis of neural activity and behavior in this task allowed us to test whether neural activity is sufficient to control movement initiation or inhibition. Surprisingly, 99% (242 of 243) of movement-related neurons in SMA and pre-SMA failed to exhibit time-locked activity changes predictive of movement initiation in this task. We also found a second group of neurons that was more active during successful response cancelation. Of these putative inhibitory cells, 18% (7 of 40) responded early enough to be able to influence the cancelation of the movement. Thus, when tested with the countermanding task, the SMA/pre-SMA region may play a role in movement inhibition but does not appear to control movement initiation. However, the activity of 76% (202 of 267) of movement-related neurons was contingent on the expectation of reward and 42% of them reflected the amount of expected reward. These findings suggest that the movement-related activity in pre-SMA and SMA might represent the motivation for a specific action but does not determine whether or not that action is performed. This motivational signal in pre-SMA and SMA could provide an essential link between reward expectation and motor execution.