Highlights d DN/IPN thalamocortical activity conveys a reliable feedforward motor timing signal d Silencing DN/IPN or recipient regions of thalamus blocks movement initiation d Photostimulation of the DN/IPN thalamocortical pathway triggers movement d Thalamocortical activation drives behavioral contextdependent movement initiation

The dorsal nucleus of the lateral lemniscus (DNLL) is an auditory brain stem structure that generates a long-lasting GABAergic output, which is important for binaural processing. Despite its importance in binaural processing, little is known about the cellular physiology and the synaptic input kinetics of DNLL neurons. To assess the relevant physiological parameters of DNLL neurons, their late postnatal developmental profile was analyzed in acute brain slices of 9- to 26-day-old Mongolian gerbils. The observed developmental changes in passive membrane and action potential (AP) properties all point toward an improvement of fast and precise signal integration in these neurons. Accordingly, synaptic glutamatergic and GABAergic current kinetics accelerate with age. The changes in intrinsic and synaptic properties contribute nearly equally to reduce the latency and jitter in AP generation and thus enhance the temporal precision of DNLL neurons. Furthermore, the size of the synaptic NMDA current is developmentally downregulated. Despite this developmental reduction, DNLL neurons display an NMDA-dependent postsynaptic amplification of AP generation, known to support high firing rates, throughout this developmental period. Taken together, our findings indicate that during late postnatal development DNLL neurons are optimized for high firing rates with high temporal precision.

Franzen DL, Gleiss SA, Berger C, Kümpfbeck FS, Ammer JJ, Felmy F. Development and modulation of intrinsic membrane properties control the temporal precision of auditory brain stem neurons. J Neurophysiol 113: 524 -536, 2015. First published October 29, 2014 doi:10.1152/jn.00601.2014.-Passive and active membrane properties determine the voltage responses of neurons. Within the auditory brain stem, refinements in these intrinsic properties during late postnatal development usually generate short integration times and precise action-potential generation. This developmentally acquired temporal precision is crucial for auditory signal processing. How the interactions of these intrinsic properties develop in concert to enable auditory neurons to transfer information with high temporal precision has not yet been elucidated in detail. Here, we show how the developmental interaction of intrinsic membrane parameters generates high firing precision. We performed in vitro recordings from neurons of postnatal days 9 -28 in the ventral nucleus of the lateral lemniscus of Mongolian gerbils, an auditory brain stem structure that converts excitatory to inhibitory information with high temporal precision. During this developmental period, the input resistance and capacitance decrease, and action potentials acquire faster kinetics and enhanced precision. Depending on the stimulation time course, the input resistance and capacitance contribute differentially to action-potential thresholds. The decrease in input resistance, however, is sufficient to explain the enhanced action-potential precision. Alterations in passive membrane properties also interact with a developmental change in potassium currents to generate the emergence of the mature firing pattern, characteristic of coincidence-detector neurons. Cholinergic receptormediated depolarizations further modulate this intrinsic excitability profile by eliciting changes in the threshold and firing pattern, irrespective of the developmental stage. Thus our findings reveal how intrinsic membrane properties interact developmentally to promote temporally precise information processing.ventral nucleus of the lateral lemniscus; postnatal development; neuronal excitability; cholinergic modulation THE ABILITY OF A NEURON TO generate action potentials with high temporal precision depends on the interaction of passive and active membrane properties (Ammer et al.

Neuronal encoding and collective network activity depend on the precise mechanism for generating action potentials. A dynamic switch in this mechanism could greatly expand the functional repertoire of neurons and circuits. Here we show that changes in neuronal biophysics control a complex, yet fundamental, sequence of dynamic transitions in neuronal excitability in which neurons switch from integrators to resonators near the spike threshold, from simple voltage dynamics to the bistable co-existence of action potentials and quiescence, and from continuous class-I to discontinuous class-II firing rate encoding. Using multiple bifurcation theory, we prove that this transition sequence is universal in conductance-based neurons. Using dynamic-clamp and pharmacology, we show experimentally that an increase in leak conductance or application of the inhibitory agonist GABA can dynamically induce these transitions in hippocampal and brainstem neurons. Our results imply that synaptic activity can flexibly control resonance, excitability and bistability of neurons. In simulated neuronal networks, we show that such synaptically induced transitions provide a mechanism for the dynamic gating of input signals and the targeted synchronization of sub-networks with a tunable number of neurons. SignificanceNeuronal function depends on the mechanism by which neurons transform synaptic input into action potentials (APs). It is unclear how neurons might control the AP mechanism to systematically modulate their responses to input signals or their collective behavior. Here we identify a complex, but model-independent, universal sequence of transitions in the dynamics of AP generation. Using patch-clamp recordings, we show that synaptic receptor activation can flexibly change the AP dynamics, confirming our theoretical predictions: non-resonant neurons develop a sub-threshold resonance, become bistable, and develop an abrupt jump in onset AP frequency. Our results explain how synapses or neuro-modulators could control neuronal excitability, influence information processing, and processing during collective network dynamics.

Different mechanisms for action potential (AP) generation exist that shape neuronal coding and network dynamics. The neuro-transmitter GABA regulates neuronal activity but its role in modulating AP dynamics itself is unclear. Here we show that GABA indeed changes the AP mechanism: it causes regularly firing hippocampal CA3 neurons to bistably switch between spiking and quiescence, converts graded discharge-tocurrent relationships to have abrupt onsets, and induces resonance. Modeling reveals that A-currents enable these GABA-induced transitions. Mathematically, we prove that this transition sequence originates from a single universal principle that generically underlies the modulation of AP dynamics in any conductance-based neuron model. Conductance clamp experiments in hippocampal and brainstem neurons show the same transitions, confirming the universal theory. In simulated networks, synaptically controlled AP dynamics, permits dynamic gating of signals and targeted synchronization of neuronal sub-ensembles. These results advance the systematic understanding of AP modulation and its role in neuronal and network function.

In the auditory system, large somatic synapses convey strong excitation that supports temporally precise information transfer. The information transfer of such synapses has predominantly been investigated in the endbulbs of Held in the anterior ventral cochlear nucleus and the calyx of Held in the medial nucleus of the trapezoid body. These large synapses either work as relays or integrate over a small number of inputs to excite the postsynaptic neuron beyond action potential (AP) threshold. In the monaural system, another large somatic synapse targets neurons in the ventral nucleus of the lateral lemniscus (VNLL). Here, we comparatively analyze the mechanisms of synaptic information transfer in endbulbs in the VNLL and the calyx of Held in juvenile Mongolian gerbils. We find that endbulbs in the VNLL are functionally surface-scaled versions of the calyx of Held with respect to vesicle availability, release efficacy, and synaptic peak currents. This functional scaling is achieved by different calcium current kinetics that compensate for the smaller AP in VNLL endbulbs. However, the average postsynaptic current in the VNLL fails to elicit APs in its target neurons, even though equal current suffices to generate APs in neurons postsynaptic to the calyx of Held. In the VNLL, a postsynaptic A-type outward current reduces excitability and prevents AP generation upon a single presynaptic input. Instead, coincidence detection of inputs from two converging endbulbs is ideal to reliably trigger APs. Thus, even large endbulbs do not guarantee one-to-one AP transfer. Instead, information flow appears regulated by circuit requirements.

Tel. +44 131 650 3113 53 Email: Ian.Duguid@ed.ac.uk 54 65 Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-66 evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral 67 context, but generated semi-random movements in an altered behavioral context. Thus, 68 cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of 69 motor commands that initiate goal-directed movement, refining our understanding of how the 70 cerebellar-thalamocortical pathway contributes to movement timing. 71 72 129 ( Figure 1c and Video S1). Mice rapidly learned to execute the task (mean = 7.5 days, 95% CI 130 [6.3, 8.6], N = 16 mice, all data, unless otherwise stated, are presented as mean, 131 [bootstrapped 95% confidence interval]; last session task success, mean = 0.64 rewards per 132 cue presentation, 95% CI [0.56, 0.72]), displaying relatively fast reaction times (last session, 133 median = 0.32s [0.30, 0.34]) and reproducible forelimb kinematic trajectories (Figures 1d-1f, 134 Video S1).135 136

To capture the context of sensory information, neural networks must process input signals across multiple timescales. In the auditory system, a prominent change in temporal processing takes place at an inhibitory GABAergic synapse in the dorsal nucleus of the lateral lemniscus (DNLL). At this synapse, inhibition outlasts the stimulus by tens of milliseconds, such that it suppresses responses to lagging sounds, and is therefore implicated in echo suppression. Here, we untangle the cellular basis of this inhibition. We demonstrate with in vivo whole-cell patch-clamp recordings in Mongolian gerbils that the duration of inhibition increases with sound intensity. Activity-dependent spillover and asynchronous release translate the high presynaptic firing rates found in vivo into a prolonged synaptic output in acute slice recordings. A key mechanism controlling the inhibitory time course is the passive integration of the hyperpolarizing inhibitory conductance. This prolongation depends on the synaptic conductance amplitude. Computational modeling shows that this prolongation is a general mechanism and relies on a non-linear effect caused by synaptic conductance saturation when approaching the GABA reversal potential. The resulting hyperpolarization generates an efficient activity-dependent suppression of action potentials without affecting the threshold or gain of the input-output function. Taken together, the GABAergic inhibition in the DNLL is adjusted to the physiologically relevant duration by passive integration of inhibition with activity-dependent synaptic kinetics. This change in processing timescale combined with the reciprocal connectivity between the DNLLs implements a mechanism to suppress the distracting localization cues of echoes and helps to localize the initial sound source reliably.