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 GoldingFunded by NIMH, NIDCD and NSF.

• Computational and experimental study – coincidence detection and ITD coding (gerbil MSO, in vitro)

• Subthreshold dynamic negative feedback: GKLT activ’n; phasic firing; brief temporal integration window; integration of noisy inputs (STA)

•The definitive feedforword neuron: bipolar dendrites and distrib’n of Iion

• Coding: •population coding (slope or place code?); role of inhibition; role of EPSP asymmetries + IKLT;• stimulus dependent filter/selectivity.

In vivo data from the barn owl shows NL neurons encode ITD

A

B

C

D

E

PLACE CODEOUTPUTS

DE

LA

Y L

INE

IN

PU

TS

DE

LA

Y L

INE

INP

UT

S

C

ITD sensitivity arises from a coincidence detection mechanism, as in the Jeffress model

5

left ear leads right ear leadsINTERAURAL TIME DIFFERENCE (µsec)

100

50

0

4409 Hz

0-300

-150 150 300

-30 µsec

% M

AX

IMU

M R

ESP

ON

SE

… place code or slope code?

• in vivo gerbil: ITD-tuning peak is outside physiol range.

• Inhibition shapes ITD-tuning.

Brand et al. Nature, 2002

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.

INa fairly inactivated near rest.

J Neurosci, 2002

HH-type model with currents: INa IKHT

and subthreshold IKLT

INa

IKHT

IKLT

mV

msec

mV

Phasic firing properties

0

30

0 80

KLT

ThKLTKLTm

nVnn

tIVVnGVGVC

VThKLT

VTh

I

V

Idealized model: integrate and fire with “IKLT”

Network, 2003.

Slow ramp: no spike

Fast ramp:one spike

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

IKLT narrows temporal integration window.

Notice “dip”: IKLT is partially active at rest;transient hyperpolarization promotes spiking by deactivating IKLT.

-8 -6 -4 -2 0

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.

+-

++

--

“MSO”cell

+-

++

--

+-

++

--

++-

++

--

“MSO”cell

Poisson PSGs from Nex + Ninh input fibers

spont rate

Some expts: Detection of subthreshold signal amidst noisy background

+-

++

--

“MSO”cell

+-

++

--

+-

++

--

++-

++

--

“MSO”cell

Poisson PSGs from Nex + Ninh input fibers

DTX (IKLT 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 “Isyn”, expeimental

Selectivity endowed by IKLT depends on spectralprofile of the input. w/ Day, Doiron J Neurophys, 2008.

• Rothman-Manis (HH-type) 2003 model: Dynamic vs Frozen IKLT

• Noisy input I(t); STEs {IST(tj)} discrete time ti 2 clouds in vector space• Discriminant analysis (feature extraction) finds “direction”

that maximizes “distance” between clouds (Fisher criterion) projections of {IST(tj)}• For white noise input: no difference in STAs.

150 Hz

650 Hz

Stim selec’n diff’ce (SSD)= 1-misclassification error

Coincidence detection – a role for dendrites

Gradient of length alongtonotopic axis.

Agmon-Snir, Carr, Rinzel: Nature ‘98

Reduction of“false positives”

Compartmental model; 2-variable minimal phasic model

“HH-type” cable model, based on I,V-clamp data (in vitro, gerbil, Golding, 2006).

gex(t), τex=0.2 ms

spike generation

gKLT in S, IS and weak in D;active or “frozen” (passive);

gNa only in Axon.

Biophysical model: gerbil MSO -- dendritesw/ P Jercog and Golding lab … ongoing

l/λ ≈ 0.6-0.8τm ≈ 0.6-1 ms

EPSP attenuation and temporal sharpening - subthreshold

Experiment Golding lab + V-clamp

Theory Jercog, Rinzel

If gKLT is “frozen”.

0.5 ms

5 mV

73 µm

Dendrite 35 µm

55 µm

Soma 80

60

40

20

0

EPS

P a

mpl

. (m

V)

100806040200Propagation distance (µm)

Dend Soma Dual Somatic

Attenuation and sharpening grow with propagation distance in model.

Experiment

Theory

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

Motion direction sensitivity. Passive cable, Rall (1964).

“directionselectivity”

Proximal to distal sequence: rapid rise, broad EPSP at soma.

Distal to proximal sequence: latency, buildup to higher peak EPSP.

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

τex=0.2 … spike τex=0.5 no spike

Include axonalspike generation

Synaptic input must be fast for spike generation.

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.

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?

ITD

ipsi contra

Δ

ITD tuning in small mammals issensitive to timed inhibition slope code

Brand et al, Nature, 2002

Results with MSO cell model. Rothman et al ’93

Key parameters:τinh= 0.1 ms, Δ = 0.2 ms

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 IKLT before fast rise to threshold – lowering probability to fire.

Ipsi leading Contra leading

Contra EPSPs slower than Ipsi EPSPs

Asymmetry in EPSPs shapes ITD tuningw/ 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.

Effect of inhibition -- counteracts the advantage of faster-rising ipsi inputs...

τinh = 2 ms

With inhibition

Inhibition blocked

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 GoldingFunded by NIMH, NIDCD and NSF.

• Computational and experimental study – coincidence detection and ITD coding (gerbil MSO, in vitro)

• Subthreshold dynamic negative feedback: GKLT activ’n; phasic firing; brief temporal integration window; integration of noisy inputs (STA)

•The definitive feedforword neuron: bipolar dendrites and distrib’n of Iion

• Coding: •population coding (slope or place code?); role of inhibition; role of EPSP asymmetries + IKLT;• stimulus dependent filter/selectivity.