cnbh university of essex 1 inhibitory and excitatory influences in the cochlear nucleus revealed...

CNBH University of EssexCNBH University of Essex

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Inhibitory and excitatory Inhibitory and excitatory influences in the cochlear nucleus influences in the cochlear nucleus

revealed using revealed using a forward masking paradigm.a forward masking paradigm.

Ray Meddis

CNBH, Hearing Research LaboratoryDepartment of Psychology, The University of Essex,

Susan ShoreKresge Hearing Research Institute,

University of Michigan and Medical College of Ohio.

BSA September 1999 at The University of Essex.


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AbstractAbstractForward-masking effects can be observed in single units in the ventral cochlear nucleus (VCN) as reductions in the spike rate in response to a probe tone presented soon after the cessation of a masker tone (Shore, 1995). The response is likely to be determined by a number of different influences, including adaptation of the auditory nerve (AN), local and centrifugal excitation and inhibition. We present an analysis technique whose purpose is to segregate these influences and determine which influences are common to different cell types. Recordings were made in the VCN using a forward-masking paradigm consisting of a 50-ms pure-tone masker followed by a 20-ms probe tone after a variable delay. A range of response types were studied: primarylike (PL), primarylike with notch (PN), onset chopper (ON), sustained chopper (CS), low intensity chopper (CL) and transient chopper (CT). The data were collected before and after a surgical cut in the brainstem that isolated the CN from other nuclei (Shore, 1998). The difference in response to the onset of the probe tone between the before-cut and after-cut data was attributed to centrifugal influences on the cell. These influences can be further segregated by decomposing the recovery function into component exponential functions. We can use the time constants of these functions to identify each influence. No two cell-types showed the same pattern of influences but some influences applied to many different types of cells. For example, all cells except ON cells appear to be receiving centrifugal inhibition with a 15-ms decay time-constant. Similarly, all cells except CS cells appear to be subject to a centrifugal excitatory influence with a 24-ms decay time-constant. The after-cut data suggest that most cells are responding to a source of excitation (presumably from the AN) recovering with a time constant of 90 ms. The analysis also suggests hypotheses that can be tested pharmacologically.


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IntroductionIntroductionBasic approach.

The response of a single cell in the VCN can be viewed as the sum of a set of component influences.

Following the offset of the masker, each component will decay or recover with its own characteristic time constant.

We assume that these processes will be exponential and that each component can be identified in terms of its characteristic time constant.

VCN

cell

AN

recovery

Within CN

inhibition

Centrifugal

inhibition

Centrifugal

excitation


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Data acquisitionData acquisitionThe data are from recordings of single units in the ventral cochlear nucleus (VCN) of guinea pigs and are fully reported in Shore (1998).

Classification of units Primarylike (PL); Primarylike with notch (PN); Chopper with sustained chopping throughout (CS); Chopper which became irregular after 4 chopping peaks (CT); Chopper chopping only at low intensities (CL); Onset response with low level later activity (ON)

Stimuli 50-msec masker at BF (20 dB SL) followed by 20-msec probe (15 dB SL) after a variable interval (∆t = {5 - 200 msec} )

Response Rate of firing during the first two milliseconds of the probe stimulus, normalised to the rate obtained in the absence of a masker.

Surgical section 5 mm rostral-caudal knife cut directed through the cerebellum and brainstem to a position just medial to the CN intended to eliminate input from superior olivary complex, contralateral CN and inferior colliculus. Recordings were made before and after the cut.

Data used Data are the responses averaged over all units of a given type. Before-cut (172 units) and after-cut (134 units) data sometimes come from the same animal but different cells. 43 animals were used in total.


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ObservationsObservations VCN units respond with a lower

firing rate to the onset of a brief (20 msec) probe tone (at BF) following exposure to a 50-msec masking tone of the same frequency.

Responsiveness is lowest immediately following the cessation of the masker but recovers over a 200 msec period.

The recovery functions are different in different units. The differences across unit types reflect differences in inputs to the units.

0

1

0 200∆t

PLONCSCTPNCL

before-cut data

Time since masker offset


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ObservationsObservations

0

1

0 200∆t

PLONCSCTPNCL

after-cut data When a surgical incision is made

isolating the CN from other brainstem nuclei, the recovery functions are different.

This implies that the recovery of firing rate is normally influenced by a ‘centrifugal effect’.

The effect differs from one cell type to another.


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The difference between the ‘before-cut’ and ‘after-cut’ data was calculated

‘After-cut’ data is assumed to reflect inputs from the auditory nerve (AN) and within-CN effects.

‘Difference’ data are assumed to reflect influences from outside the CN and is named the ‘centrifugal effect’.

In this example, the data for sustained chopping units is used. Note that the difference or ‘centrifugal effect’ is largely, but not exclusively, decaying inhibition.

Centrifugal effectsCentrifugal effects

-2

-1

0

1

2

0 200∆t

before-cut

after-cut

difference (centrifugal )

CS effect of cut


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Each recovery function is modelled as the sum of up to two exponential recovery functions.

In this example, the CS centrifugal effect was modelled as the sum of an excitatory and a suppressive exponential influence.

Where:

Component functions - centrifugalComponent functions - centrifugal

rt =k1 +a1e−Δt

τ1 +a2e−Δt

τ2

a1= -2.3τ1= 15 msec2=a 2.1τ2= 9 msec2=k 0.0

-2

-1

0

1

0 200∆t

difference (centrifugal )

excitatory

suppressive

ex + suppr + constant

CS analysis of centrifugal effect


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‘After-cut’ data are modeled here as two recovery functions - one fast and one slow.

Where:

rt =1−(k2 +a3e−Δt

τ3 +a4e−Δt

τ4 )

a3= 1.1τ13= 4 msec4=a 0.1τ4= 90 msec2=k 0.0

0

1

0 200∆t

data

slow recovery

fast recovery

sum: 1-(slow+fast+constant)

CS analysis of after-cut response

Component functions - after-cutComponent functions - after-cut


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Data analysisData analysis Fits were improved using Excel ‘solver’ function.

With so many parameters, there is no simple route to the best-fit solution. Initial parameters were suggested by the first author.

Fits were based on minimum absolute error (difference between data and model). The fits reported are the best obtained after extensive searching (largely trial and error).

The analysis was constrained to minimise the number of different time constants in the 24 functions, while maintaining a good fit. Only 12 time constants were used when 24 were possible.

Any function whose coefficient, ai, was smaller than 0.05 was omitted from the analysis


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Numerical resultsNumerical results

Colours group time constants that may represent effects from a common source.

PL ON CS CT PN CLcentrifugal

a1 -0.6 -1.0 -2.3 -0.9 -2.5 -1.8τ1 15 86 15 15 15 15

2a 0.4 2.1 0.7 2.1 1.4τ2 24 9 24 24 24

1k 0.0 0.3 0.0 0.0 0.0 0.1

after cut3a -0.2 1.1 0.3 -0.1

τ3 6 4 13 6 4a 0.6 0.9 0.1 0.5 1.0 0.6

τ4 90 27 90 90 48 902k 0.0 0.0 0.0 0.0 0.2 0.0

rt =k1 +a1e−Δt

τ1 +a2e−Δt

τ2

rt =1−(k2 +a3e−Δt

τ3 +a4e−Δt

τ4 )


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Centrifugal effectsCentrifugal effectsgraphical summarygraphical summary

Suppressivecentrifugal effect

τ =15 msec

Excitatorycentrifugal effect

τ =24 msec

τ =9 msec

τ =86 msec

PL PN CT CL CS ON --unit type

Suppressivecentrifugal effect

Excitatorycentrifugal effect

Strength of influence

Is reflected in line thickness


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Ascending/local effectsAscending/local effectsgraphical summarygraphical summary

Decaying suppressive effects (may include AN recovery)

τ =90 msec

τ = 6 msec

PL PN CT CL CS ON

τ=48 msec τ =27 msecτ =13 msec

Decaying excitatory effects

--unit type

τ =4 msec


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The model results were obtained by adding all four exponential functions and two constants. They are compared with data from the intact animal

0

1

0 200

∆t

PL

0

1

0 200

∆t

ON

0

1

0 200

∆t

CS

0

1

0 200

∆t

CT

0

1

0 200

∆t

PN

0

1

0 200

∆t

CL

Fit of model to ‘before-cut’ dataFit of model to ‘before-cut’ data

rt =k1 +a1e−Δt

τ1 +a2e−Δt

τ2 +1−(k2 +a3e−Δt

τ3 +a4e−Δt

τ4)


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Predictions using the modelPredictions using the modelOne test of the model results is to

predict the effect of pharmacological intervention.

The black line shows the response of the intact animal.

We predict the effect of eliminating an influence by setting the corresponding coefficient ai to zero.

The blue line predicts the outcome if the inhibitory effect can be eliminated pharmacologically.

The red line predicts the outcome if the excitatory input can be eliminated. Negative values imply no response should be observed.

CT

-1

0

1

0 200∆t

remove inhibition

remove excitation

data (before-cut)


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DiscussionDiscussion This analysis was devised after the collection of the data. More data points in

the recovery functions will make the results more secure. With so many parameters, there is no guarantee that the best solution can be found. However, the commonalities across cell types look secure.

The 90 msec time constant of recovery for ‘after-cut’ data observed in five unit types is likely to come from AN inputs. Chimento and Schreiner (1991) measured similar AN recovery time constants in this region for the cat for those AN units that showed only a single recovery time constant.

The origin of the 27 msec time constant in the ON ‘after-cut’ data may have a parallel in Chimento and Schreiner’s other type of AN unit that had a double time constant of recovery (mean= 22 msec and 184 msec). However, a 184 ms recovery time-constant could not be fitted to the ON data.

The time-constants in the‘centrifugal’ data suggest that most units receive both excitatory and inhibitory inputs from two common sources higher in the brainstem. A range of possibilities exist in terms of descending connections from the superior olive and nuclei of the trapeziod body.


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ReferencesReferencesShore, S. E., Hear. Res. 1995, 82: 31-43

Shore, S. E., J. Acoust. Soc. Am. 1998, 104, 378-389

Chimento, T.C. and Schreiner, C.E. J. Acoust. Soc. Am. 90, 263-273

cnbh university of essex 1 inhibitory and excitatory influences in the cochlear nucleus revealed...

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