SUMMARY STATEMENT 

PROGRAM CONTACT: ( Privileged Communication ) Release Date: 12/07/2016 

Revised Date: 

Application Number: 2 R01 DC012557-06 

Principal Investigator 

FROEMKE, ROBERT CROOKS 

Applicant Organization: 

Review Group: ZRG1 AUD-Z (90) 

Center for Scientific Review Special Emphasis Panel 

Auditory System Special Review 

Meeting Date: 11/07/2016 

Council: JAN 2017 

Requested Start: 04/01/2017 

RFAIPA: PA16-160 

PCC: HR61 

Dual /C{s): MH, LM 

Project Title: Synaptic basis of perceptual learning in primary auditory cortex 

SRG Action: Impact Score:11 Percentile:1 & 

Next Steps: Visit http://grants.nih.gov/grants/next_steps.htm

Human Subjects: 10-No human subjects involved 

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted 

Project 

Year 

6 

7 

8 

9 

10 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 

SUMMARY STATEMENT 

PROGRAM CONTACT: ( Privileged Communi cation ) Release Date: 12/07/2016 

Revised Date: 

Application Number: 2 R01 DC012557-06 

Principal Investigator 

FROEMKE, ROBERT CROOKS 

Applicant Organization: 

Review Group: ZRG1 AUD-Z (90) 

Center for Scientific Review Speci al Emphasis Panel 

Auditory System Special Review 

Meeting Date: 11/07/2016 

Council: JAN 2017 

Requested Statt: 04/01/2017 

RFAIPA: PA16-160 

PCC: HR61 

Dual IC(s}: MH, LM 

Project Title: Synapti c basis of perceptual learning in primary auditory cortex 

SRG Action: Impact Score:11 Percentile:1 & 

Next Steps: Visit http://grants.nih.gov/grants/next steps.htm 

Human Subjects: 10-No human subjects involved 

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted 

Project 

Year 

6 

7 

a 

9 

10 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is p l anned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 
2 R01 DC012557-06 2 ZRG1 AUD-Z (90)

FROEMKE, R 

2R01DC012557-06 FROEMKE, ROBERT

RESUME AND SUMMARY OF DISCUSSION: The work proposed in this R01 renewal application is 

designed to examine the role of the cholinergic and noradrenergic neuromodulatory systems during the 

regulation of synaptic plasticity in the auditory cortex during auditory perceptual learning. Sophisticated 

methods will be used, including optogenetics, two-photon imaging and electrophysiological recordings 

in behaving mice. The panel considered this work of very high significance given the importance of the 

modulatory systems in question, the limited understanding and study of them in this context, and the 

prospect for this work to make important discoveries relevant to both the basic and translational science 

of the auditory system. Other noted strengths included the outstanding investigator, the technically 

impressive methods, the rigorously designed research strategy, with a strong scientific premise and 

ample preliminary data, “astounding productivity” in the prior funding period, and the fact that this work 

is a very logical extension of the studies in the prior funding period. No significant weaknesses were 

discussed, and panel widely agreed that the proposed work will lead to very high impact advances 

relevant to the regulation of synaptic plasticity during auditory learning.

DESCRIPTION (provided by applicant): The brain has the remarkable capability to change in 

response to experience. This plasticity is essential for learning and memory, and is an important feature 

of the auditory cortex, especially for learning the significance of sensory signals such as speech, for the 

use of devices such as cochlear implants, and for recovery after short- term deafness. These changes 

are thought to occur primarily at synapses, basic units of information processing and plasticity. Longterm synaptic plasticity requires sensory experience and activation of neuromodulatory systems which 

convey behavioral context to local cortical circuits. However, little is known about the interactions 

between synaptic inputs and release of neuromodulators in vivo, making it challenging to relate 

perceptual learning to plasticity in the auditory cortex or other brain areas. Recently we developed an 

approach to measuring dynamics of synaptic modifications for hours, coupled with imaging techniques 

enabling us to monitor the same cells over days during training, directly monitoring and manipulating 

activity in behaving mice. These approaches allow for a close examination of links between modulation, 

cortical plasticity and auditory perceptual learning. Specifically, we will study how auditory perceptual 

training activates the cholinergic vs noradrenergic modulatory systems. These two modulators are 

principally involved in selective attention towards behaviorally-important stimuli, general arousal, and 

learning. However, there may be important functional differences in these systems in terms of when 

they are active during different phases of training or consequences of cholinergic and noradrenergic 

modulation on auditory neurons for contextual information processing. This proposal describes a series 

of imaging, recording, optogenetic, and behavioral experiments that will compare and contrast the 

effects of locus coeruleus activation and norepinephrine release vs the effects of nucleus basalis 

activation and cholinergic modulation on the primary auditory cortex of behaving mice. Many studies 

have highlighted the importance of recording in awake animals during behavior, and we will first 

examine how ensembles of excitatory and inhibitory neurons are affected by learning over the entire 

duration of training, as animals go from naïve and poor performers, to having reliable performance on 

an auditory detection and recognition task we have used in the lab for years. Next, we determine when 

and how cholinergic and noradrenergic modulation affect behavioral and neural responses. Finally, we 

will make some of the first direct measurements of modulatory neuron responses, asking how these 

systems are activated by task-relevant variables such as sounds linked to reward. In summary, here 

we use in vivo recording and imaging methods to ask how behavioral training engages and modifies 

noradrenergic and cholinergic systems, to collectively affect auditory cortical processing and 

persistently improve auditory perceptual abilities in behaving mice.

PUBLIC HEALTH RELEVANCE: Neuroplasticity- the ability of the brain to change in response to 

experience- is an essential feature of the auditory cortex, especially for speech and language learning 

as well as the successful use of devices such as cochlear implants. However, it is unclear how 

motivational state and behavioral training drive plasticity within the central auditory system. The 

experiments to be performed in this proposal provide essential data on basic mechanisms of 

2 ROI DC012557-06 

FROEMKE, R 

2R01 DC012557-06 FROEMKE, ROBERT 

2 ZRG1 AUD-Z (90) 

RESUME AND SUMMARY OF DISCUSSION: The work proposed in this R01 renewal application is 

designed to examine the role of the cholinergic and noradrenergic neuromodulatory systems during the 

regulation of synaptic plasticity in the auditory cortex during auditory perceptual learning. Sophisticated 

methods will be used, including optogenetics, two-photon imaging and electrophysiological recordings 

in behaving mice. The panel considered this work of very high significance given the importance of the 

modulatory systems in question, the limited understanding and study of them in this context, and the 

prospect for this work to make important discoveries relevant to both the basic and translational science 

of the auditory system. Other noted strengths included the outstanding investigator, the technically 

impressive methods, the rigorously designed research strategy, with a strong scientific premise and 

ample preliminary data, "astounding productivity" in the prior funding period, and the fact that this work 

is a very logical extension of the studies in the prior funding period. No significant weaknesses were 

discussed, and panel widely agreed that the proposed work will lead to very high impact advances 

relevant to the regulation of synaptic plasticity during auditory learning. 

DESCRIPTION (provided by applicant): The brain has the remarkable capability to change in 

response to experience. This plasticity is essential for learning and memory, and is an important feature 

of the auditory cortex, especially for learning the significance of sensory signals such as speech, for the 

use of devices such as cochlear implants, and for recovery after short- term deafness. These changes 

are thought to occur primarily at synapses, basic units of information processing and plasticity. Longterm synaptic plasticity requires sensory experience and activation of neuromodulatory systems which 

convey behavioral context to local cortical circuits. However, little is known about the interactions 

between synaptic inputs and release of neuromodulators in vivo, making it challenging to relate 

perceptual learning to plasticity in the auditory cortex or other brain areas. Recently we developed an 

approach to measuring dynamics of synaptic modifications for hours, coupled with imaging techniques 

enabling us to monitor the same cells over days during training, directly monitoring and manipulating 

activity in behaving mice. These approaches allow for a close examination of links between modulation, 

cortical plasticity and auditory perceptual learning. Specifically, we will study how auditory perceptual 

training activates the cholinergic vs noradrenergic modulatory systems. These two modulators are 

principally involved in selective attention towards behaviorally-important stimuli, general arousal, and 

learning. However, there may be important functional differences in these systems in terms of when 

they are active during different phases of training or consequences of cholinergic and noradrenergic 

modulation on auditory neurons for contextual information processing. This proposal describes a series 

of imaging, recording, optogenetic, and behavioral experiments that will compare and contrast the 

effects of locus coeruleus activation and norepinephrine release vs the effects of nucleus basalis 

activation and cholinergic modulation on the primary auditory cortex of behaving mice. Many studies 

have highlighted the importance of recording in awake animals during behavior, and we will first 

examine how ensembles of excitatory and inhibitory neurons are affected by learning over the entire 

duration of training, as animals go from na"i"ve and poor performers, to having reliable performance on 

an auditory detection and recognition task we have used in the lab for years. Next, we determine when 

and how cholinergic and noradrenergic modulation affect behavioral and neural responses. Finally, we 

will make some of the first direct measurements of modulatory neuron responses, asking how these 

systems are activated by task-relevant variables such as sounds linked to reward. In summary, here 

we use in vivo recording and imaging methods to ask how behavioral training engages and modifies 

noradrenergic and cholinergic systems, to collectively affect auditory cortical processing and 

persistently improve auditory perceptual abilities in behaving mice. 

PUBLIC HEALTH RELEVANCE: Neuroplasticity- the ability of the brain to change in response to 

experience- is an essential feature of the auditory cortex, especially for speech and language learning 

as well as the successful use of devices such as cochlear implants. However, it is unclear how 

motivational state and behavioral training drive plasticity within the central auditory system. The 

experiments to be performed in this proposal provide essential data on basic mechanisms of 
2 R01 DC012557-06 3 ZRG1 AUD-Z (90)

FROEMKE, R 

neuromodulation and plasticity in the auditory cortex, required for improvement of prosthetic design and 

therapeutic strategies for treatment of deafness and language disorders.

Critique 1

Significance: 1

Investigator(s): 1

Innovation: 1

Approach: 2

Environment: 1

Overall Impact: The cholinergic and noradrenergic systems are clearly important modulators of neural 

activity, acting directly at the synapse and being heavily involved in learning. Auditory learning is 

important, particularly in early human life, and yet the effect of these neuromodulators in auditory cortex 

receives precious little attention. The proposal is a continuation in Dr. Froemke’s study of the effect of 

neuromodulators on learning and plasticity in the auditory pathway. The results obtained in this study, 

as well as during his previous grant cycle, are bound to have a major influence on our view of the role 

of motivation and environment in language acquisition, language disorders as well as the retraining 

necessary following cochlear implantation. 

1. Significance:

Strengths 

 This proposal builds on results and on-going research from the investigator’s previous RO1 

grant on the same subject. 

 Impressive amount of research was conducted, and results published, over the last few years, 

with more results coming. 

 As mentioned in the previous application, and still very much true, the studies of the cholinergic 

and noradrenergic systems complement existing studies of modulation of activity in auditory 

cortex (including top-down, circuit modulation), adding important new information about the role 

and importance of these neuromodulatory transmitters.

Weaknesses

 None really. The proposal was quite dense and a bit hard to read at times. Fewer details 

sometimes make points easier to grasp. 

2. Investigator(s):

Strengths 

 Impressive publication record and productivity in general. 

Weaknesses

 None

3. Innovation:

Strengths

 Many modern techniques are used. Their use is always justified. This is a difficult subject with 

comparatively little background to go on, and Dr. Froemke does an outstanding job at 

disentangling the relative contributions of the different neuromodulators under study. 

2 ROI DC012557-06 

FROEMKE, R 

3 ZRG1 AUD-Z (90) 

neuromodulation and plasticity in the auditory cortex, required for improvement of prosthetic design and 

therapeutic strategies for treatment of deafness and language disorders. 

Critique 1 

Significance: 1 

lnvestigator(s): 1 

Innovation: 1 

Approach: 2 

Environment: 1 

Overall Impact: The cholinergic and noradrenergic systems are clearly important modulators of neural 

activity, acting directly at the synapse and being heavily involved in learning. Auditory learning is 

important, particularly in early human life, and yet the effect of these neuromodulators in auditory cortex 

receives precious little attention. The proposal is a continuation in Dr. Froemke's study of the effect of 

neuromodulators on learning and plasticity in the auditory pathway. The results obtained in this study, 

as well as during his previous grant cycle, are bound to have a major influence on our view of the role 

of motivation and environment in language acquisition, language disorders as well as the retraining 

necessary following cochlear implantation. 

1. Significance: 

Strengths 

• This proposal builds on results and on-going research from the investigator's previous R01 

grant on the same subject. 

• Impressive amount of research was conducted, and results published, over the last few years, 

with more results coming. 

• As mentioned in the previous application, and still very much true, the studies of the cholinergic 

and noradrenergic systems complement existing studies of modulation of activity in auditory 

cortex (including top-down, circuit modulation), adding important new information about the role 

and importance of these neuromodulatory transmitters. 

Weaknesses 

• None really. The proposal was quite dense and a bit hard to read at times. Fewer details 

sometimes make points easier to grasp. 

2. lnvestigator(s): 

Strengths 

• Impressive publication record and productivity in general. 

Weaknesses 

• None 

3. Innovation: 

Strengths 

• Many modern techniques are used. Their use is always justified. This is a difficult subject with 

comparatively little background to go on, and Dr. Froemke does an outstanding job at 

disentangling the relative contributions of the different neuromodulators under study. 
2 R01 DC012557-06 4 ZRG1 AUD-Z (90)

FROEMKE, R 

Weaknesses

 None

4. Approach:

Strengths

 Systematic, thorough and well informed of previous research, including in related fields.

 Ongoing publication record speaks best as an answer to this question!

Weaknesses

 Proposal is quite dense and a bit hard to follow at times

 Minor: All drugs are applied bilaterally but is there laterality of some of the effects? How do both

auditory cortices keep synchrony in effect size, for example.

5. Environment:

Strengths

 NYU School of Medicine has all the resources necessary to accomplish the work proposed.

Weaknesses

 None

Protections for Human Subjects:

Not Applicable (No Human Subjects)

Vertebrate Animals:

YES, all four points addressed

 This is well justified, with much more details than are usually found.

 Both sexes will be used, but sex as a variable should be addressed more explicitly.

Biohazards:

Acceptable

Renewal:

 The very impressive body of published work that arose from the first 5 years of this grant speaks

volumes about the proposer's ability to carry work to completion.

Resource Sharing Plans:

Acceptable

Authentication of Key Biological and/or Chemical Resources:

Acceptable

Budget and Period of Support:

2 ROI DC012557-06 

FROEMKE, R 

Weaknesses 

• None 

4. Approach: 

Strengths 

4 ZRG1 AUD-Z (90) 

• Systematic, thorough and well informed of previous research, including in related fields. 

• Ongoing publication record speaks best as an answer to this question! 

Weaknesses 

• Proposal is quite dense and a bit hard to follow at times 

• Minor: All drugs are applied bilaterally but is there laterality of some of the effects? How do both 

auditory cortices keep synchrony in effect size, for example. 

5. Environment: 

Strengths 

• NYU School of Medicine has all the resources necessary to accomplish the work proposed. 

Weaknesses 

• None 

Protections for Human Subjects: 

Not Applicable (No Human Subjects) 

Vertebrate Animals: 

YES, all four points addressed 

• This is well justified, with much more details than are usually found. 

• Both sexes will be used, but sex as a variable should be addressed more explicitly. 

Biohazards: 

Acceptable 

Renewal: 

• The very impressive body of published work that arose from the first 5 years of this grant speaks 

volumes about the proposer's ability to carry work to completion. 

Resource Sharing Plans: 

Acceptable 

Authentication of Key Biological and/or Chemical Resources: 

Acceptable 

Budget and Period of Support: 
2 R01 DC012557-06 5 ZRG1 AUD-Z (90)

FROEMKE, R 

Recommend as Requested

Critique 2

Significance: 2

Investigator(s): 1

Innovation: 2

Approach: 1

Environment: 1

Overall Impact: This is a proposal for continuation of a successful research program on 

neuromodulation in auditory cortex plasticity. The reviewers found the proposed research to be a logical 

continuation of previous work, well justified by current knowledge and precisely calibrated to advance 

our understanding of one of the most interesting problems in neuroscience, the role of neural plasticity 

in learning and the relationship between behavioral learning and brain mechanisms. The proposal is 

well developed and exciting. 

1. Significance:

Strengths

 The proposed work is directed at questions of considerable current interest, for both basic and

translational science.

 The proposal is a natural evolution of the ideas and results derived from the PI’s previous work,

carrying the analysis from phenomena to mechanisms.

 The proposal builds on a strong foundation of research on the role of neuromodulators in

learning, demonstrated by behavioral and neurophysiological research. Thus the ideas are

sharply focused and there are clear and testable hypotheses.

Weaknesses

 None noted

2. Investigator(s):

Strengths

 Froemke is a very successful early-to-mid career neuroscientist. He has extensive experience

with all the research tools needed for this work.

 The PI’s laboratory has been very productive over the first 5 years of this grant support.

Weaknesses

 None

3. Innovation:

Strengths

 The techniques to be used here are state of the art in cortical neurophysiology. The PI has

marshaled the most powerful and appropriate combination of methods for each of the aims of

the proposal.

 The proposal to directly record in NB and LC is an important addition to the analysis of cortical

plasticity.

Weaknesses

2 ROI DC012557-06 

FROEMKE, R 

Recommend as Requested 

Critique 2 

Significance: 2 

lnvestigator(s): 1 

Innovation: 2 

Approach: 1 

Environment: 1 

5 ZRG1 AUD-Z (90) 

Overall Impact: This is a proposal for continuation of a successful research program on 

neuromodulation in auditory cortex plasticity. The reviewers found the proposed research to be a logical 

continuation of previous work, well justified by current knowledge and precisely calibrated to advance 

our understanding of one of the most interesting problems in neuroscience, the role of neural plasticity 

in learning and the relationship between behavioral learning and brain mechanisms. The proposal is 

well developed and exciting. 

1. Significance: 

Strengths 

• The proposed work is directed at questions of considerable current interest, for both basic and 

translational science. 

• The proposal is a natural evolution of the ideas and results derived from the Pl's previous work, 

carrying the analysis from phenomena to mechanisms. 

• The proposal builds on a strong foundation of research on the role of neuromodulators in 

learning, demonstrated by behavioral and neurophysiological research. Thus the ideas are 

sharply focused and there are clear and testable hypotheses. 

Weaknesses 

• None noted 

2. lnvestigator(s): 

Strengths 

• Froemke is a very successful early-to-mid career neuroscientist. He has extensive experience 

with all the research tools needed for this work. 

• The Pl's laboratory has been very productive over the first 5 years of this grant support. 

Weaknesses 

• None 

3. Innovation: 

Strengths 

• The techniques to be used here are state of the art in cortical neurophysiology. The Pl has 

marshaled the most powerful and appropriate combination of methods for each of the aims of 

the proposal. 

• The proposal to directly record in NB and LC is an important addition to the analysis of cortical 

plasticity. 

Weaknesses 
2 R01 DC012557-06 6 ZRG1 AUD-Z (90)

FROEMKE, R 

 None noted

4. Approach:

Strengths

 The planned experiments are a systematic and logical sequence proceeding from the properties

of cortical neurons, to the dependence of those properties on the ACh and NE systems, to the

response characteristics of the neuromodulatory source neurons.

 The ability to study neurons with both intracellular (whole-cell) and population (2-photon)

recording will yield a comprehensive view of the neural activity.

 The plan to separate excitatory from inhibitory inputs in whole-cell recording is a powerful

approach to analysis of synaptic plasticity.

 Preliminary data are provided to show that the proposed experiments can be successfully done

in the PI’s laboratory.

 Multiple technical approaches are planned for most of the aims. Thus, if something doesn't

work, there’s usually another approach in reserve.

 Appropriate plans for statistical testing are given in the methods and the number of animals to

be used is determined on the basis of the expected statistical power of the data.

Weaknesses

 None noted

5. Environment:

Strengths

 The PI’s laboratory is well-equipped. Most of the equipment needed for the proposed work is

contained in the lab or in the PI’s department. Some needed equipment and upgrades will be

added in year 3.

 The Institute is an excellent environment for the proposed work with good colleagues for 

support and scientific discussions. The PI seems to be well-mentored.

Weaknesses

 None noted

Protections for Human Subjects:

Not Applicable (No Human Subjects)

Vertebrate Animals:

YES, all four points addressed

 The use of mice and the animal numbers is well justified by the proposed work. Both male and

female animals will be used. There is adequate veterinary care available and the procedures to

minimize discomfort are appropriate. The euthanasia plan is satisfactory.

Biohazards:

Not Applicable (No Biohazards)

2 ROI DC012557-06 

FROEMKE, R 

• None noted 

4. Approach: 

Strengths 

6 ZRG1 AUD-Z (90) 

• The planned experiments are a systematic and logical sequence proceeding from the properties 

of cortical neurons, to the dependence of those properties on the ACh and NE systems, to the 

response characteristics of the neuromodulatory source neurons. 

• The ability to study neurons with both intracellular (whole-cell) and population (2-photon) 

recording will yield a comprehensive view of the neural activity. 

• The plan to separate excitatory from inhibitory inputs in whole-cell recording is a powerful 

approach to analysis of synaptic plasticity. 

• Preliminary data are provided to show that the proposed experiments can be successfully done 

in the Pl's laboratory. 

• Multiple technical approaches are planned for most of the aims. Thus, if something doesn't 

work, there's usually another approach in reserve. 

• Appropriate plans for statistical testing are given in the methods and the number of animals to 

be used is determined on the basis of the expected statistical power of the data. 

Weaknesses 

• None noted 

5. Environment: 

Strengths 

• The Pl's laboratory is well-equipped. Most of the equipment needed for the proposed work is 

contained in the lab or in the Pl's department. Some needed equipment and upgrades will be 

added in year 3. 

• The-Institute is an excellent environment for the proposed work with good colleagues for 

support and scientific discussions. The Pl seems to be well-mentored. 

Weaknesses 

• None noted 

Protections for Human Subjects: 

Not Applicable (No Human Subjects) 

Vertebrate Animals: 

YES, all four points addressed 

• The use of mice and the animal numbers is well justified by the proposed work. Both male and 

female animals will be used. There is adequate veterinary care available and the procedures to 

minimize discomfort are appropriate. The euthanasia plan is satisfactory. 

Biohazards: 

Not Applicable (No Biohazards) 
2 R01 DC012557-06 7 ZRG1 AUD-Z (90)

FROEMKE, R 

Renewal:

 Progress during the previous grant period has been very good. The previous work lays an

excellent foundation for the work proposed here.

Authentication of Key Biological and/or Chemical Resources:

Acceptable

Budget and Period of Support:

Recommend as Requested

Critique 3

Significance: 2

Investigator(s): 1

Innovation: 2

Approach: 1

Environment: 2

Overall Impact: This is a well-written renewal that proposes a logical extension of some very 

successful studies focused on plasticity in auditory cortex. The underlying premise is that acetylcholine 

and noradrenaline modulate auditory cortex during contextual learning. The new studies will use highly 

innovative optogenetic and imaging methods in awake animals to monitor cholinergic and 

noradrenergic modulation of task-related plasticity in primary auditory cortex. The results will move the 

field forward regarding the relative contributions of acetylcholine and norepinephrine in controlling the 

plasticity of excitatory and inhibitory cortical neurons during different phases of learning an auditory 

task.

1. Significance:

Strengths

 These experiments promise a unique opportunity to dissect the differential contributions of

acetylcholine and noerepinephrine to inter-related contributions to plasticity and learning of an

auditory task.

Weaknesses

 None

2. Investigator(s):

Strengths

 The PI has been a leader in developing many of the techniques to be used in the current

studies.

Weaknesses

 None

3. Innovation:

2 ROI DC012557-06 

FROEMKE, R 

Renewal: 

7 ZRG1 AUD-Z (90) 

• Progress during the previous grant period has been very good. The previous work lays an 

excellent foundation for the work proposed here. 

Authentication of Key Biological and/or Chemical Resources: 

Acceptable 

Budget and Period of Support: 

Recommend as Requested 

Critique 3 

Significance: 2 

lnvestigator(s): 1 

Innovation: 2 

Approach: 1 

Environment: 2 

Overall Impact: This is a well-written renewal that proposes a logical extension of some very 

successful studies focused on plasticity in auditory cortex. The underlying premise is that acetylcholine 

and noradrenaline modulate auditory cortex during contextual learning. The new studies will use highly 

innovative optogenetic and imaging methods in awake animals to monitor cholinergic and 

noradrenergic modulation of task-related plasticity in primary auditory cortex. The results will move the 

field forward regarding the relative contributions of acetylcholine and norepinephrine in controlling the 

plasticity of excitatory and inhibitory cortical neurons during different phases of learning an auditory 

task. 

1. Significance: 

Strengths 

• These experiments promise a unique opportunity to dissect the differential contributions of 

acetylcholine and noerepinephrine to inter-related contributions to plasticity and learning of an 

auditory task. 

Weaknesses 

• None 

2. lnvestigator(s): 

Strengths 

• The Pl has been a leader in developing many of the techniques to be used in the current 

studies. 

Weaknesses 

• None 

3. Innovation: 
2 R01 DC012557-06 8 ZRG1 AUD-Z (90)

FROEMKE, R 

Strengths

 Simultaneous examination of ACh and NE axon activity in primary auditory cortex.

Weaknesses

 None

4. Approach:

Strengths

 Rigor is addressed appropriately. Both sexes will be used. Strains are discussed appropriately.

Group sizes are determined appropriately.

 The proposed work forms a logical extension of previous work in that it looks at NE and ACH

simultaneously; 2) it looks at effects in un-anesthetized animals.

 Substantial preliminary data suggests shows a high likelihood for success of the experiments.

 The 3 Aims represent independent but highly related experiments that together produce a

logical set of results that will move the field forward regardless of the particular findings.

Weaknesses

 Two-photon imaging is largely limited to the superficial layers of cortex, preventing the

experimenters from collecting data from neurons in the deeper layers in certain experiments.

The advantages of this approach probably outweigh the limitations, but the PI acknowledges the

compromise.

5. Environment:

Strengths

 NYU provides an outstanding intellectual environment

 All necessary equipment is available, with local expertise in abundance for troubleshooting any

problems that might arise

Weaknesses

 None

Protections for Human Subjects:

Not Applicable (No Human Subjects)

Vertebrate Animals:

YES, all four points addressed

Renewal:

 The PI has been highly productive during the last grant period.

 The proposed experiments represent a logical extension of the previous work.

Budget and Period of Support:

Recommend as Requested

2 ROI DC012557-06 

FROEMKE, R 

Strengths 

8 ZRG1 AUD-Z (90) 

• Simultaneous examination of ACh and NE axon activity in primary auditory cortex. 

Weaknesses 

• None 

4. Approach: 

Strengths 

• Rigor is addressed appropriately. Both sexes will be used. Strains are discussed appropriately. 

Group sizes are determined appropriately. 

• The proposed work forms a logical extension of previous work in that it looks at NE and ACH 

simultaneously; 2) it looks at effects in un-anesthetized animals. 

• Substantial preliminary data suggests shows a high likelihood for success of the experiments. 

• The 3 Aims represent independent but highly related experiments that together produce a 

logical set of results that will move the field forward regardless of the particular findings. 

Weaknesses 

• Two-photon imaging is largely limited to the superficial layers of cortex, preventing the 

experimenters from collecting data from neurons in the deeper layers in certain experiments. 

The advantages of this approach probably outweigh the limitations, but the Pl acknowledges the 

compromise. 

5. Environment: 

Strengths 

• NYU provides an outstanding intellectual environment 

• All necessary equipment is available, with local expertise in abundance for troubleshooting any 

problems that might arise 

Weaknesses 

• None 

Protections for Human Subjects: 

Not Applicable (No Human Subjects) 

Vertebrate Animals: 

YES, all four points addressed 

Renewal: 

• The Pl has been highly productive during the last grant period. 

• The proposed experiments represent a logical extension of the previous work. 

Budget and Period of Support: 

Recommend as Requested 
2 R01 DC012557-06 9 ZRG1 AUD-Z (90)

FROEMKE, R 

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO 

SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' 

WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES:

VERTEBRATE ANIMAL (Resume): ACCEPTABLE

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested.

Footnotes for 2 R01 DC012557-06; PI Name: FROEMKE, ROBERT CROOKS

& Ad hoc or special section application percentiled against 2017/01 AUD study section.

NIH has modified its policy regarding the receipt of resubmissions (amended applications). 

See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOTOD-14-074.html. The impact/priority score is calculated after discussion of an application by

averaging the overall scores (1-9) given by all voting reviewers on the committee and

multiplying by 10. The criterion scores are submitted prior to the meeting by the individual

reviewers assigned to an application, and are not discussed specifically at the review meeting

or calculated into the overall impact score. Some applications also receive a percentile

ranking. For details on the review process, see

http://grants.nih.gov/grants/peer_review_process.htm#scoring.

2 ROI DC012557-06 

FROEMKE, R 

9 ZRG1 AUD-Z (90) 

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO 

SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' 

WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: 

VERTEBRATE ANIMAL (Resume): ACCEPTABLE 

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. 

Footnotes for 2 R01 DC012557-06; Pl Name: FROEMKE, ROBERT CROOKS 

& Ad hoc or special section application percentiled against 2017/01 AUD study section. 

NIH has modified its policy regarding the receipt of resubmissions (amended applications). 

See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOTOD-14-074.html. The impact/priority score is calculated after discussion of an application by 

averaging the overall scores (1-9) given by all voting reviewers on the committee and 

multiplying by 10. The criterion scores are submitted prior to the meeting by the individual 

reviewers assigned to an application, and are not discussed specifically at the review meeting 

or calculated into the overall impact score. Some applications also receive a percentile 

ranking. For details on the review process, see 

http://grants.nih.gov/grants/peer review process.htm#scoring.