The capacity to use tools is a fundamental evolutionary achievement. Its essence stands in the capacity to transfer a proximal goal (grasp a tool) to a distal goal (e.g., grasp food). Where and how does this goal transfer occur? Here, we show that, in monkeys trained to use tools, cortical motor neurons, active during hand grasping, also become active during grasping with pliers, as if the pliers were now the hand fingers. This motor embodiment occurs both for normal pliers and for ''reverse pliers,'' an implement that requires finger opening, instead of their closing, to grasp an object. We conclude that the capacity to use tools is based on an inherently goal-centered functional organization of primate cortical motor areas.neurophysiology ͉ tool use ͉ goal coding ͉ motor act

Mirror neurons are a distinct class of neurons that discharge both during the execution of a motor act and during observation of the same or similar motor act performed by another individual. However, the extent to which mirror neurons coding a motor act with a specific goal (e.g., grasping) might also respond to the observation of a motor act having the same goal, but achieved with artificial effectors, is not yet established. In the present study, we addressed this issue by recording mirror neurons from the ventral premotor cortex (area F5) of two monkeys trained to grasp objects with pliers. Neuron activity was recorded during the observation and execution of grasping performed with the hand, with pliers and during observation of an experimenter spearing food with a stick. The results showed that virtually all neurons responding to the observation of hand grasping also responded to the observation of grasping with pliers and, many of them to the observation of spearing with a stick. However, the intensity and pattern of the response differed among conditions. Hand grasping observation determined the earliest and the strongest discharge, while pliers grasping and spearing observation triggered weaker responses at longer latencies. We conclude that F5 grasping mirror neurons respond to the observation of a family of stimuli leading to the same goal. However, the response pattern depends upon the similarity between the observed motor act and the one executed by the hand, the natural motor template.

Activation of nicotinic acetylcholine receptors (nAChRs) by systemic nicotine enhances sensory-cognitive function and sensory-evoked cortical responses. Although nAChRs mediate fast neurotransmission at many synapses in the nervous system, nicotinic regulation of cortical processing is neuromodulatory. To explore potential mechanisms of nicotinic neuromodulation, we examined whether intracellular signal transduction involving mitogen-activated protein kinase (MAPK) contributes to regulation of tone-evoked responses in primary auditory cortex (A1) in the mouse. Systemic nicotine enhanced characteristic frequency (CF) tone-evoked current-source density (CSD) profiles in A1, including the shortest-latency (presumed thalamocortical) current sink in layer 4 and longer-latency (presumed intracortical) sinks in layers 2-4, by increasing response amplitudes and decreasing response latencies. Microinjection of the MAPK kinase (MEK) inhibitor U0126 into the thalamus, targeting the auditory thalamocortical pathway, blocked the effect of nicotine on the initial (thalamocortical) CSD component but did not block enhancement of longer-latency (intracortical) responses. Conversely, microinjection of U0126 into supragranular layers of A1 blocked nicotine's effect on intracortical, but not thalamocortical, CSD components. Simultaneously with enhancement of CF-evoked responses, responses to spectrally distant (nonCF) stimuli were reduced, implying nicotinic "sharpening" of frequency receptive fields, an effect also blocked by MEK inhibition. Consistent with these physiological results, acoustic stimulation with nicotine produced immunolabel for activated MAPK in A1, primarily in layer 2/3 cell bodies. Immunolabel was blocked by intracortical microinjection of the nAChR antagonist dihydro-β-erythroidine, but not methyllycaconitine, implicating α4β2*, but not α7, nAChRs. Thus activation of MAPK in functionally distinct forebrain circuits--thalamocortical, local intracortical, and long-range intracortical--underlies nicotinic neuromodulation of A1.

Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral “notch” of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.

Auditory-cued behavioral training can alter neural circuits in primary auditory cortex (A1), but the mechanisms and consequences of experience-dependent cortical plasticity are not fully understood. To address this issue, we trained adult rats to detect a 5 kHz target in order to receive a food reward. After 14 days training we identified three locations within A1: i) the region representing the characteristic frequency (CF) 5 kHz, ii) a nearby region with CF ~10 kHz, and iii) a more distant region with CF ~20 kHz. In order to compare functional connectivity in A1 near to, vs. far from, the representation of the target frequency, we placed a 16-channel multiprobe in middle- (~10 kHz) and high- (~20 kHz) CF regions and obtained current-source density (CSD) profiles evoked by a range of tone stimuli (CF ± 1–3 octaves in quarter-octave steps). Our aim was to construct “CSD receptive fields” (CSD RFs) in order to determine the laminar and spectral profile of tone-evoked current sinks, and infer changes to thalamocortical and intracortical inputs. Behavioral training altered CSD RFs at the 10 kHz, but not 20 kHz, site relative to CSD RFs in untrained control animals. At the 10 kHz site, current sinks evoked by the target frequency were enhanced in layer 2/3, but the initial current sink in layer 4 was not altered. The results imply training-induced plasticity along intracortical pathways connecting the target representation with nearby cortical regions. Finally, we related behavioral performance (sensitivity index, d′) to CSD responses in individual animals, and found a significant correlation between the development of d′ over training and the amplitude of the target-evoked current sink in layer 2/3. The results suggest that plasticity along intracortical pathways is important for auditory learning.