Fast A-type currents shape a rapidly adapting form of delayed short latency firing of excitatory superficial dorsal horn neurons that express the NPY Y1 receptor

ABSTRACTNeuroanatomical and behavioral evidence indicates that neuropeptide Y Y1 receptor-expressing interneurons (Y1-INs) in the superficial dorsal horn (SDH) are predominantly excitatory and contribute to chronic pain. Using an adult ex vivo spinal cord slice preparation from Y1eGFP reporter mice, we characterized firing patterns in response to steady state depolarizing current injection of GFP-positive cells in lamina II, the great majority of which expressed Y1 mRNA (88%). Randomly sampled and Y1eGFP neurons exhibited five firing patterns: tonic (TF), initial burst (IBF), phasic (PF), delayed short-latency <180 ms (DSLF), and delayed long-latency >180 ms (DLLF). When studied at resting membrane potential, most RS neurons exhibited delayed firing, while most Y1eGFP neurons exhibited phasic firing and not delayed firing. A preconditioning membrane hyperpolarization produced only subtle changes in the firing patterns of randomly sampled neurons, but dramatically shifted Y1eGFP neurons to DSLF (46%) and DLLF (24%). In contrast to randomly sampled DSLF neurons which rarely exhibited spike frequency adaptation, Y1eGFP DSLF neurons were almost always rapidly adapting, a characteristic of nociceptive-responsive SDH neurons. Rebound spiking was more prevalent in Y1eGFP neurons (6% RS vs 32% Y1eGFP), indicating enrichment of T-type calcium currents. Y1eGFP DSLF neurons exhibited fast A-type potassium currents that are known to delay or limit action potential firing, and these were of smaller current density as compared to randomly sampled DSLF neurons. Our results inspire future studies to determine whether tissue or nerve injury downregulates channels that contribute to A-currents, thus potentially unmasking T-type calcium channel activity and membrane hyperexcitability in Y1-INs, leading to persistent pain.KEYPOINTSNeuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain.For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice.Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF).Y1eGFP DSLF neurons were almost always rapidly adapting and often exhibited rebound spiking, characteristics of spinal pain neurons under the control of T-type calcium channels.These results inspire future studies to determine whether tissue or nerve injury downregulates the channels that underlie A-currents, thus unmasking membrane hyperexcitability in Y1- expressing dorsal horn neurons, leading to persistent pain

Optogenetic activation of the inhibitory nigro-collicular circuit evokes orienting movements in mice

ABSTRACTIn contrast to predictions from the current model of basal ganglia (BG) function, we report here that increasing inhibition from the BG to the superior colliculus (SC) through the substantia nigra (nigra) using in vivo optogenetic activation of GABAergic terminals in mice, produces contralateral orienting movements. Orienting movements resulting from activation of inhibitory nigral terminals are unexpected because decreases and not increases, in nigral activity are generally associated with orienting movements. To determine how orienting movements may result from activation of inhibitory terminals, we performed a series of slice experiments and found that the same optogenetic stimulation of nigral terminals used in vivo, evoked post-inhibitory rebound depolarization and spiking in SC output neurons in vitro. Only high frequency (100Hz) stimulation evoked contralateral movements in vivo and triggered rebound spiking in vitro. The latency of orienting movements relative to the stimulation in vivo was similar to the latency of rebound spiking in vitro. Taken together, our results point toward a novel hypothesis that inhibition from the BG may play an active rather than passive role in the generation of orienting movements in mice.

Basal ganglia and cortical control of thalamic rebound spikes

Basal ganglia output neurons transmit motor signals by decreasing their firing rate during movement. This decrease can lead to post-inhibitory rebound spikes in thalamocortical neurons in motor thalamus. While in healthy animals neural activity in the basal ganglia is markedly uncorrelated, in Parkinson’s disease neural activity becomes pathologically correlated. Here we investigated the impact of correlations in the basal ganglia output on the transmission of motor signals to motor thalamus using a Hodgkin-Huxley model of a thalamocortical neuron. We found that correlations in the basal ganglia output disrupt the transmission of motor signals via rebound spikes by decreasing the signal-to-noise ratio and increasing the trial-to-trial variability. We further examined the role of brief sensory responses in basal ganglia output neurons and the effect of cortical excitation of motor thalamus in modulating rebound spiking. Interestingly, both the sensory responses and cortical inputs could either promote or suppress the generation of rebound spikes depending on their timing relative to the motor signal. Finally, in the model rebound spiking occurred despite the presence of moderate levels of excitation, indicating that rebound spiking might be feasible in a parameter regime relevant also in vivo. Overall, our model provides novel insights into the transmission of motor signals from the basal ganglia to motor thalamus by suggesting new functional roles for active decorrelation and sensory responses in the basal ganglia, as well as cortical excitation of motor thalamus.

Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations

Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type ( wt), spasmodic ( spd), spastic ( spa), and oscillator ( ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by “gain” in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., Δ I) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot.

Neuronal rebound spiking, resonance frequency and theta cycle skipping may contribute to grid cell firing in medial entorhinal cortex

Data show a relationship of cellular resonance and network oscillations in the entorhinal cortex to the spatial periodicity of grid cells. This paper presents a model that simulates the resonance and rebound spiking properties of entorhinal neurons to generate spatial periodicity dependent upon phasic input from medial septum. The model shows that a difference in spatial periodicity can result from a difference in neuronal resonance frequency that replicates data from several experiments. The model also demonstrates a functional role for the phenomenon of theta cycle skipping in the medial entorhinal cortex.

Development of on-off spiking in superior paraolivary nucleus neurons of the mouse

The superior paraolivary nucleus (SPON) is a prominent cell group in the auditory brain stem that has been increasingly implicated in representing temporal sound structure. Although SPON neurons selectively respond to acoustic signals important for sound periodicity, the underlying physiological specializations enabling these responses are poorly understood. We used in vitro and in vivo recordings to investigate how SPON neurons develop intrinsic cellular properties that make them well suited for encoding temporal sound features. In addition to their hallmark rebound spiking at the stimulus offset, SPON neurons were characterized by spiking patterns termed onset, adapting, and burst in response to depolarizing stimuli in vitro. Cells with burst spiking had some morphological differences compared with other SPON neurons and were localized to the dorsolateral region of the nucleus. Both membrane and spiking properties underwent strong developmental regulation, becoming more temporally precise with age for both onset and offset spiking. Single-unit recordings obtained in young mice demonstrated that SPON neurons respond with temporally precise onset spiking upon tone stimulation in vivo, in addition to the typical offset spiking. Taken together, the results of the present study demonstrate that SPON neurons develop sharp on-off spiking, which may confer sensitivity to sound amplitude modulations or abrupt sound transients. These findings are consistent with the proposed involvement of the SPON in the processing of temporal sound structure, relevant for encoding communication cues.