1. Sound localization and timing computations in the auditory brain stem. J Rinzel, NYU with G Svirskis, R Dodla, V Kotak, D Sanes, M Day, B Doiron, P Jercog, N Golding Funded by NIMH, NIDCD and NSF. Computational and experimental study – coincidence detection and ITD coding (gerbil MSO, in vitro) Subthreshold dynamic negative feedback: G KLT activ’n; phasic firing; brief temporal integration window; integration of noisy inputs (STA) The definitive feedforword neuron: bipolar dendrites and distrib’n of I ion Coding: population coding (slope or place code?); role of inhibition; role of EPSP asymmetries + I KLT ; stimulus dependent filter/selectivity.

2. In vivo data from the barn owl shows NL neurons encode ITD A B C D E PLACE CODE OUTPUTS DELAY LINE INPUTS C ITD sensitivity arises from a coincidence detection mechanism, as in the Jeffress model 5 left ear leads right ear leads INTERAURAL TIME DIFFERENCE (µsec) 100 50 0 4409 Hz 0 -300 -150150300 -30 µsec % MAXIMUM RESPONSE

3. … place code or slope code? in vivo gerbil: ITD-tuning peak is outside physiol range. Inhibition shapes ITD-tuning. Brand et al. Nature, 2002

4. MSO neurons fire phasically, not to slow inputs. Blocking I KLT may convert to tonic. J Neurosci, 2002 Even after reducing I KLT, some neurons (older) remained phasic. I Na fairly inactivated near rest.

5. J Neurosci, 2002 HH-type model with currents: I Na I KHT and subthreshold I KLT I Na I KHT I KLT mV msec mV Phasic firing properties Idealized model: integrate and fire with “I KLT ” Network, 2003.

6. Slow ramp: no spike Fast ramp: one spike

7. Schematic of circuit for low frequency coincidence detection in mammals. (D Sanes w/ focus on gerbil.)

8. I KLT narrows temporal integration window. Notice “dip”: I KLT is partially active at rest; transient hyperpolarization promotes spiking by deactivating I KLT. -8-6-4-20 0.0 0.1 0.2 time before spike, ms I, nA leaky I&F + IKLT leaky I&F leaky I&F + IKLT below RMP Spike-generating current by reverse correlation. Network, 2003. Poisson PSGs from N ex + N inh input fibers spont rate Some expts: Detection of subthreshold signal amidst noisy background

9. Poisson PSGs from N ex + N inh input fibers DTX (I KLT blocker) ==> -- widening of integration window -- reduction of “dip” J Neurosci, 2002 Control After DTX Response of MSO cell to brief “signal” in noise. Spike triggered average “I syn ”, expeimental

10. Selectivity endowed by I KLT depends on spectral profile of the input. w/ Day, Doiron J Neurophys, 2008. Rothman-Manis (HH-type) 2003 model: Dynamic vs Frozen I KLT Noisy input I(t); STEs {I ST (t j )} discrete time t i  2 clouds in vector space Discriminant analysis (feature extraction) finds “direction” that maximizes “distance” between clouds (Fisher criterion)  projections of {I ST (t j )} For white noise input: no difference in STAs. 150 Hz 650 Hz Stim selec’n diff’ce (SSD)= 1-misclassification error

11. Coincidence detection – a role for dendrites Gradient of length along tonotopic axis. Agmon-Snir, Carr, Rinzel: Nature ‘98 Reduction of “false positives” Compartmental model; 2-variable minimal phasic model

12. “HH-type” cable model, based on I,V-clamp data (in vitro, gerbil, Golding, 2006). g ex (t), τ ex =0.2 ms spike generation g KLT in S, IS and weak in D; active or “frozen” (passive); g Na only in Axon. Biophysical model: gerbil MSO -- dendrites w/ P Jercog and Golding lab … ongoing l/λ ≈ 0.6-0.8 τ m ≈ 0.6-1 ms

13. EPSP attenuation and temporal sharpening - subthreshold Experiment Golding lab + V-clamp Theory Jercog, Rinzel If g KLT is “frozen”.

14. Attenuation and sharpening grow with propagation distance in model. Experiment Theory

15. Time difference sensitivity, enhanced for inputs to dendrite – subthreshold case.

16. Motion direction sensitivity. Passive cable, Rall (1964). “direction selectivity” Proximal to distal sequence: rapid rise, broad EPSP at soma. Distal to proximal sequence: latency, buildup to higher peak EPSP.

17. Response to “near then far” input is disadvantaged by wake of (dendritic) g KLT along path to Soma.

18. τ ex =0.2 … spike τ ex =0.5 no spike Include axonal spike generation Synaptic input must be fast for spike generation.

19. Coincidence detection in model… with spikes in axon the definitive feedforward neuron. “ITD” = 0.1 ms“ITD” = 0.15 ms No back-propagating action potential.

20. Grothe, New roles for synaptic inhibition in sound localization, Nat. Rev. (2003) ITD peak is outside physiol range Blocking inhibition shifts the ITD-tuning curve to “0”. Tuning for Interaural Time Difference (ITD), shaped by transient inhibition Contralateral excitation is preceded by inhibition. Ipsilateral excitation precedes inhibition. in vivo, gerbil Brand et al, 2002 Place code or slope code?

21. ITD ipsicontra Δ ITD tuning in small mammals is sensitive to timed inhibition  slope code Brand et al, Nature, 2002 Results with MSO cell model. Rothman et al ’93 Key parameters: τ inh = 0.1 ms, Δ = 0.2 ms

22. Asymmetry in EPSPs shapes ITD tuning In vitro thick slice  ITD in dish. w/ Jercog, Sanes, Svirksis, Kotak - ongoing If contra-EPSP is slower-rising, it recruits more I KLT before fast rise to threshold – lowering probability to fire. Ipsi leadingContra leading Contra EPSPs slower than Ipsi EPSPs

23. Asymmetry in EPSPs shapes ITD tuning w/ Jercog, Sanes, Svirksis, Kotak - ongoing In vitro thick slice  ITD in dish. Contra pathway is longer  greater latency for EPSPs Contra inputs are slower rising.

24. Effect of inhibition -- counteracts the advantage of faster-rising ipsi inputs... τ inh = 2 ms With inhibition Inhibition blocked

25. Sound localization and timing computations in the auditory brain stem. J Rinzel, NYU with G Svirskis, R Dodla, V Kotak, D Sanes, M Day, B Doiron, P Jercog, N Golding Funded by NIMH, NIDCD and NSF. Computational and experimental study – coincidence detection and ITD coding (gerbil MSO, in vitro) Subthreshold dynamic negative feedback: G KLT activ’n; phasic firing; brief temporal integration window; integration of noisy inputs (STA) The definitive feedforword neuron: bipolar dendrites and distrib’n of I ion Coding: population coding (slope or place code?); role of inhibition; role of EPSP asymmetries + I KLT ; stimulus dependent filter/selectivity.