In the primary motor cortex (M1), layer 5 projection neurons signal directly to distant motor structures to drive movement. Despite their pivotal position and acknowledged diversity these neurons are traditionally separated into broad commissural and corticofugal types, and until now no attempt has been made at resolving the basis for their diversity. We therefore probed the electrophysiological and morphological properties of retrogradely labeled M1 corticospinal (CSp), corticothalamic (CTh), and commissural projecting corticostriatal (CStr) and corticocortical (CC) neurons. An unsupervised cluster analysis established at least four phenotypes with additional differences between lumbar and cervical projecting CSp neurons. Distinguishing parameters included the action potential (AP) waveform, firing behavior, the hyperpolarisation-activated sag potential, sublayer position, and soma and dendrite size. CTh neurons differed from CSp neurons in showing spike frequency acceleration and a greater sag potential. CStr neurons had the lowest AP amplitude and maximum rise rate of all neurons. Temperature influenced spike train behavior in corticofugal neurons. At 26°C CTh neurons fired bursts of APs more often than CSp neurons, but at 36°C both groups fired regular APs. Our findings provide reliable phenotypic fingerprints to identify distinct M1 projection neuron classes as a tool to understand their unique contributions to motor function.

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In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.

Pauses in the tonic firing of striatal cholinergic interneurons emerge during reward-related learning and are triggered by neutral cues which develop behavioural significance. In a previous in vivo study we have proposed that these pauses in firing may be due to intrinsically generated afterhyperpolarisations (AHPs) evoked by excitatory synaptic inputs, including those below the threshold for action potential firing. The aim of this study was to investigate the mechanism of the AHPs using a brain slice preparation which preserved both cerebral hemispheres. Augmenting cortically evoked postsynaptic potentials (PSPs) by repetitive stimulation of cortical afferents evoked AHPs that were unaffected by blocking either GABA A receptors with bicuculline, or GABA B receptors with saclofen or CGP55845. Apamin (a blocker of small conductance Ca 2+ -activated K + channels) had minimal effects, while chelation of intracellular Ca 2+ with BAPTA reduced the AHP by about 30%. In contrast, blocking hyperpolarisation and cyclic nucleotide activated (HCN) cation current (I H ) with ZD7288 or Cs + diminished the size of the AHPs by 60% and reduced the proportion of episodes that contained this hyperpolarisation. The reversal potential (−20 mV) and voltage dependence of the AHPs were consistent with the hypothesis that a transient deactivation of I H caused most of the AHP at hyperpolarised potentials, while the slow AHP-type Ca 2+ -activated K + channels increasingly contributed at more depolarised membrane potentials. Subthreshold somatic current injections yielded similar AHPs with a median duration of ∼700 ms that were not affected by firing of a single action potential. These results indicate that transient deactivation of HCN channels evokes pauses in tonic firing of cholinergic interneurons, an event likely to be elicited by augmentation of afferent synaptic inputs during learning.