@article{
 title = {Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome},
 type = {article},
 year = {2022},
 keywords = {Dravet syndrome,GABAergic interneurons,Nav1.1,SCN1A,epilepsy},
 pages = {110580},
 volume = {38},
 websites = {https://linkinghub.elsevier.com/retrieve/pii/S2211124722003242},
 month = {3},
 publisher = {Cell Press},
 day = {29},
 id = {833062c0-d840-3c91-bd45-c19420d31d66},
 created = {2022-03-30T11:50:34.278Z},
 accessed = {2022-03-30},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2022-05-12T14:12:26.991Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 folder_uuids = {11b3f8d2-36c2-431a-ba82-dee5f10d76b7},
 private_publication = {false},
 abstract = {Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a+/− mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a+/− mice at postnatal days (P) 16–21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a+/− mice that did not survive and in Scn1a+/− mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome: combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology.},
 bibtype = {article},
 author = {Kaneko, Keisuke and Currin, Christopher B. and Goff, Kevin M. and Wengert, Eric R. and Somarowthu, Ala and Vogels, Tim P. and Goldberg, Ethan M.},
 doi = {10.1016/j.celrep.2022.110580},
 journal = {Cell Reports},
 number = {13}
}

Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a+/− mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a+/− mice at postnatal days (P) 16–21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a+/− mice that did not survive and in Scn1a+/− mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome: combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology.

@article{
 title = {Depolarization of echo chambers by random dynamical nudge},
 type = {article},
 year = {2022},
 pages = {9234},
 volume = {12},
 websites = {http://arxiv.org/abs/2101.04079,https://www.nature.com/articles/s41598-022-12494-w},
 month = {12},
 publisher = {Nature Publishing Group UK},
 day = {2},
 id = {d03701fa-24a7-3066-957c-4c8212d427cd},
 created = {2022-08-08T10:48:48.844Z},
 file_attached = {false},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2022-08-08T10:48:48.844Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {In social networks, users often engage with like-minded peers. This selective exposure to opinions might result in echo chambers, i.e., political fragmentation and social polarization of user interactions. When echo chambers form, opinions have a bimodal distribution with two peaks on opposite sides. In certain issues, where either extreme positions contain a degree of misinformation, neutral consensus is preferable for promoting discourse. In this paper, we use an opinion dynamics model that naturally forms echo chambers in order to find a feedback mechanism that bridges these communities and leads to a neutral consensus. We introduce the random dynamical nudge (RDN), which presents each agent with input from a random selection of other agents’ opinions and does not require surveillance of every person’s opinions. Our computational results in two different models suggest that the RDN leads to a unimodal distribution of opinions centered around the neutral consensus. Furthermore, the RDN is effective both for preventing the formation of echo chambers and also for depolarizing existing echo chambers. Due to the simple and robust nature of the RDN, social media networks might be able to implement a version of this self-feedback mechanism, when appropriate, to prevent the segregation of online communities on complex social issues.},
 bibtype = {article},
 author = {Currin, Christopher Brian and Vera, Sebastián Vallejo and Khaledi-Nasab, Ali},
 doi = {10.1038/s41598-022-12494-w},
 journal = {Scientific Reports},
 number = {1}
}

In social networks, users often engage with like-minded peers. This selective exposure to opinions might result in echo chambers, i.e., political fragmentation and social polarization of user interactions. When echo chambers form, opinions have a bimodal distribution with two peaks on opposite sides. In certain issues, where either extreme positions contain a degree of misinformation, neutral consensus is preferable for promoting discourse. In this paper, we use an opinion dynamics model that naturally forms echo chambers in order to find a feedback mechanism that bridges these communities and leads to a neutral consensus. We introduce the random dynamical nudge (RDN), which presents each agent with input from a random selection of other agents’ opinions and does not require surveillance of every person’s opinions. Our computational results in two different models suggest that the RDN leads to a unimodal distribution of opinions centered around the neutral consensus. Furthermore, the RDN is effective both for preventing the formation of echo chambers and also for depolarizing existing echo chambers. Due to the simple and robust nature of the RDN, social media networks might be able to implement a version of this self-feedback mechanism, when appropriate, to prevent the segregation of online communities on complex social issues.

@article{
 title = {Depolarization of echo chambers by random dynamical nudge},
 type = {article},
 year = {2021},
 keywords = {Social networks,depolarization,echo chambers,nudge},
 websites = {http://arxiv.org/abs/2101.04079},
 month = {1},
 day = {7},
 id = {16cd7e81-79d9-336e-bb3b-7774d5dcef12},
 created = {2021-07-19T10:59:29.416Z},
 accessed = {2021-07-19},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2022-05-09T12:02:24.836Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Interactions among individuals in social networks lead to echo chambers where the distribution of opinions follows a bimodal distribution with two peaks at the opposite extremes. In issues with clear answers, such as global warming, one of the echo chambers reflects an inaccurate judgment, potentially from misinformation. However, in issues without clear answers such as elections, the neutral consensus is preferable for promoting discourse. In this letter, we use an opinion dynamics model to study the effect of a random dynamical nudge where we present random input to each agent from the other individuals in the network. We show that random dynamical nudge disallows the formation of echo chambers and leads to a normal distribution of opinions centered around the neutral consensus. The random dynamical nudge relies on the collective dynamics and it does not require surveillance of every person's opinions. Social media networks could implement a version of this self-feedback mechanism to prevent the formation of segregated online communities on pressing issues such as elections.},
 bibtype = {article},
 author = {Currin, Christopher Brian and Vera, Sebastian Vallejo and Khaledi-Nasab, Ali},
 journal = {arXiv}
}

Interactions among individuals in social networks lead to echo chambers where the distribution of opinions follows a bimodal distribution with two peaks at the opposite extremes. In issues with clear answers, such as global warming, one of the echo chambers reflects an inaccurate judgment, potentially from misinformation. However, in issues without clear answers such as elections, the neutral consensus is preferable for promoting discourse. In this letter, we use an opinion dynamics model to study the effect of a random dynamical nudge where we present random input to each agent from the other individuals in the network. We show that random dynamical nudge disallows the formation of echo chambers and leads to a normal distribution of opinions centered around the neutral consensus. The random dynamical nudge relies on the collective dynamics and it does not require surveillance of every person's opinions. Social media networks could implement a version of this self-feedback mechanism to prevent the formation of segregated online communities on pressing issues such as elections.

@article{
 title = {Computational models reveal how chloride dynamics determine the optimal distribution of inhibitory synapses to minimise dendritic excitability},
 type = {article},
 year = {2021},
 pages = {1-29},
 websites = {https://www.biorxiv.org/content/10.1101/2021.12.07.471404v1},
 id = {07d4b153-b22b-3718-8bd2-7f5564c97d1b},
 created = {2021-12-17T14:18:21.444Z},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2022-05-09T12:02:24.400Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Many neurons in the mammalian central nervous system have complex dendritic arborisations and active dendritic conductances that enable these cells to perform sophisticated computations. How dendritically targeted inhibition affects local dendritic excitability is not fully understood. Here we use computational models of branched dendrites to investigate where GABAergic synapses should be placed to minimise dendritic excitability over time. To do so, we formulate a metric we term the “Inhibitory Level” (IL), which quantifies the effectiveness of synaptic inhibition for reducing the depolarising effect of nearby excitatory input. GABAergic synaptic inhibition is dependent on the reversal potential for GABAA receptors (EGABA), which is primarily set by the transmembrane chloride ion (Cl-) concentration gradient. We, therefore, investigated how variable EGABA and dynamic chloride affects dendritic inhibition. We found that the inhibitory effectiveness of dendritic GABAergic synapses accumulates at an encircled branch junction. The extent of inhibitory accumulation is dependent on the number of branches and location of synapses but is independent of EGABA. This accumulation occurs even for very distally placed inhibitory synapses when they are hyperpolarising – but not when they are shunting. When accounting for Cl- fluxes and dynamics in Cl- concentration, we observed that Cl- loading is detrimental to inhibitory effectiveness. This enabled us to determine the most inhibitory distribution of GABAergic synapses which is close to – but not at – a shared branch junction. This distribution balances a trade-off between a stronger combined inhibitory influence when synapses closely encircle a branch junction with the deleterious effects of increased Cl- loading that occurs when inhibitory synapses are co-located.},
 bibtype = {article},
 author = {Currin, Christopher Brian and Raimondo, Joseph Valentino},
 doi = {10.1101/2021.12.07.471404v1},
 journal = {bioRxiv}
}

Many neurons in the mammalian central nervous system have complex dendritic arborisations and active dendritic conductances that enable these cells to perform sophisticated computations. How dendritically targeted inhibition affects local dendritic excitability is not fully understood. Here we use computational models of branched dendrites to investigate where GABAergic synapses should be placed to minimise dendritic excitability over time. To do so, we formulate a metric we term the “Inhibitory Level” (IL), which quantifies the effectiveness of synaptic inhibition for reducing the depolarising effect of nearby excitatory input. GABAergic synaptic inhibition is dependent on the reversal potential for GABAA receptors (EGABA), which is primarily set by the transmembrane chloride ion (Cl-) concentration gradient. We, therefore, investigated how variable EGABA and dynamic chloride affects dendritic inhibition. We found that the inhibitory effectiveness of dendritic GABAergic synapses accumulates at an encircled branch junction. The extent of inhibitory accumulation is dependent on the number of branches and location of synapses but is independent of EGABA. This accumulation occurs even for very distally placed inhibitory synapses when they are hyperpolarising – but not when they are shunting. When accounting for Cl- fluxes and dynamics in Cl- concentration, we observed that Cl- loading is detrimental to inhibitory effectiveness. This enabled us to determine the most inhibitory distribution of GABAergic synapses which is close to – but not at – a shared branch junction. This distribution balances a trade-off between a stronger combined inhibitory influence when synapses closely encircle a branch junction with the deleterious effects of increased Cl- loading that occurs when inhibitory synapses are co-located.

@article{
 title = {Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome},
 type = {article},
 year = {2021},
 keywords = {1,dravet syndrome,epilepsy,gabaergic interneurons,nav1,scn1a},
 pages = {1-45},
 websites = {https://www.biorxiv.org/content/10.1101/2021.07.28.454042v1},
 id = {b3250a8a-8fd9-34f4-8dbf-a19eddac3fa7},
 created = {2021-12-17T14:18:21.445Z},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2022-05-09T12:02:24.684Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Dravet syndrome (DS) is a neurodevelopmental disorder defined by epilepsy, intellectual disability, and sudden death, due to heterozygous variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from pre-weanling Scn1a+/− mice show impaired action potential generation. A novel approach assessing PV-IN function in the same mice at two developmental time points showed that, at post-natal day (P) 16-21, spike generation was impaired all mice, deceased prior or surviving to P35. However, synaptic transmission was selectively dysfunctional in pre-weanling mice that did not survive. Spike generation in surviving mice normalized by P35, yet we again identified abnormalities in synaptic transmission. We conclude that combined dysfunction of PV-IN spike generation and synaptic transmission drives disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology. Modeling revealed that PV-IN axonal propagation is more sensitive to decreases in sodium conductance than spike generation.},
 bibtype = {article},
 author = {Kaneko, Keisuke and Currin, Christopher B. and Goff, Kevin M. and Somarowthu, Ala and Vogels, Tim P. and Goldberg, Ethan M.},
 doi = {10.1101/2021.07.28.454042},
 journal = {bioRxiv}
}

Dravet syndrome (DS) is a neurodevelopmental disorder defined by epilepsy, intellectual disability, and sudden death, due to heterozygous variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from pre-weanling Scn1a+/− mice show impaired action potential generation. A novel approach assessing PV-IN function in the same mice at two developmental time points showed that, at post-natal day (P) 16-21, spike generation was impaired all mice, deceased prior or surviving to P35. However, synaptic transmission was selectively dysfunctional in pre-weanling mice that did not survive. Spike generation in surviving mice normalized by P35, yet we again identified abnormalities in synaptic transmission. We conclude that combined dysfunction of PV-IN spike generation and synaptic transmission drives disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology. Modeling revealed that PV-IN axonal propagation is more sensitive to decreases in sodium conductance than spike generation.

@article{
 title = {Chloride dynamics alter the input-output properties of neurons},
 type = {article},
 year = {2020},
 pages = {e1007932},
 volume = {16},
 websites = {https://dx.plos.org/10.1371/journal.pcbi.1007932},
 month = {5},
 publisher = {Public Library of Science},
 day = {26},
 id = {2f1a1aac-ba49-3395-9690-51a830ef1ee6},
 created = {2020-06-09T12:21:51.208Z},
 accessed = {2020-06-09},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2020-10-07T09:15:54.290Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 folder_uuids = {ae45c7d5-5268-47ba-b7b9-d742d4e3b7db},
 private_publication = {false},
 abstract = {Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.},
 bibtype = {article},
 author = {Currin, Christopher B. and Trevelyan, Andrew J. and Akerman, Colin J. and Raimondo, Joseph V.},
 editor = {Berry, Hugues},
 doi = {10.1371/journal.pcbi.1007932},
 journal = {PLOS Computational Biology},
 number = {5}
}

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.

@article{
 title = {Think: Theory for Africa},
 type = {article},
 year = {2019},
 pages = {e1007049},
 volume = {15},
 websites = {http://dx.plos.org/10.1371/journal.pcbi.1007049},
 month = {7},
 publisher = {Public Library of Science},
 day = {11},
 id = {d690c3c2-89de-3e42-bde9-334e99dcf442},
 created = {2019-07-18T18:58:54.448Z},
 accessed = {2019-07-18},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2019-10-31T15:55:19.135Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Currin2019a},
 folder_uuids = {2804bb52-7643-4eb6-9267-7e68a92ab57b},
 private_publication = {false},
 bibtype = {article},
 author = {Currin, Christopher B. and Khoza, Phumlani N. and Antrobus, Alexander D. and Latham, Peter E. and Vogels, Tim P. and Raimondo, Joseph V.},
 editor = {Isik, Leyla},
 doi = {10.1371/journal.pcbi.1007049},
 journal = {PLoS Computational Biology},
 number = {7}
}

@article{
 title = {Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis},
 type = {article},
 year = {2018},
 volume = {7},
 websites = {https://elifesciences.org/articles/39575},
 month = {9},
 day = {27},
 id = {ef06980f-e4cf-3cb9-a7e5-ce73c209b9e8},
 created = {2018-10-27T20:40:55.303Z},
 accessed = {2018-10-27},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2019-10-31T15:55:19.149Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Dusterwald2018},
 folder_uuids = {bf6cbabe-7a6a-4003-9dd0-f1c24e66ab8a},
 private_publication = {false},
 abstract = {Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here, we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signaling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.},
 bibtype = {article},
 author = {Düsterwald, Kira M and Currin, Christopher B and Burman, Richard J and Akerman, Colin J and Kay, Alan R and Raimondo, Joseph V},
 doi = {10.7554/eLife.39575},
 journal = {eLife}
}

Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here, we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signaling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

@article{
 title = {Early ethanol exposure and vinpocetine treatment alter learning- and memory-related proteins in the rat hippocampus and prefrontal cortex},
 type = {article},
 year = {2017},
 keywords = {BDNF,Ethanol,Learning and memory,MKP-1,Morris,Morris water maze,P-ERK1/2,P-GSK3β,[BDNF,ethanol,learning and memory,phosphodiesterase,vinpocetine},
 pages = {1204-1215},
 volume = {95},
 id = {c8168511-a182-37d8-a5bd-d4f43acd259e},
 created = {2018-10-28T11:02:48.031Z},
 file_attached = {true},
 profile_id = {14badb0b-89a9-3047-a69a-683d5240354c},
 last_modified = {2021-07-19T11:20:34.072Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {? 2016 Wiley Periodicals, Inc.This study investigates the effects of early exposure to ethanol on cognitive function and neural plasticity-related proteins in the rat brain. Sprague-Dawley rats were administered 12% ethanol solution (4g/kg/day i.p.) or saline from P4 to P9. Vinpocetine, a phosphodiesterase type 1 inhibitor, was tested to determine whether it could reverse any changes induced by early ethanol exposure. Hence, from P25 to P31, ethanol-exposed male rats were injected with vinpocetine (20mg/kg/day i.p.) or vehicle (DMSO) prior to undergoing behavioral testing in the open field and Morris water maze (MWM) tests. Ethanol exposure did not adversely affect spatial memory in the MWM. A key finding in this study was a significant ethanol-induced change in the function of the phosphorylated extracellular signal-related kinase (P-ERK) signaling pathway in the prefrontal cortex (PFC) and dorsal hippocampus (DH) of rats that did not display overt behavioral deficits. The P-ERK/ERK ratio was decreased in the PFC and increased in the DH of ethanol-exposed rats compared with controls. Rats that received vinpocetine in addition to ethanol did not display any behavioral changes but did show alterations in neural plasticity-related proteins. Mitogen-activated protein kinase phosphatase was increased, whereas brain-derived neurotrophic factor was decreased, in the PFC of vinpocetine-treated ethanol-exposed rats, and phosphorylated-glycogen synthase kinase ? and synaptophysin were increased in the DH of these rats. This study provides insight into the long-term effects of early ethanol exposure and its interaction with vinpocetine in the rat brain.},
 bibtype = {article},
 author = {Swart, Patricia C. and Currin, Christopher B. and Russell, Vivienne A. and Dimatelis, Jacqueline J.},
 doi = {10.1002/jnr.23894},
 journal = {Journal of Neuroscience Research},
 number = {5}
}

? 2016 Wiley Periodicals, Inc.This study investigates the effects of early exposure to ethanol on cognitive function and neural plasticity-related proteins in the rat brain. Sprague-Dawley rats were administered 12% ethanol solution (4g/kg/day i.p.) or saline from P4 to P9. Vinpocetine, a phosphodiesterase type 1 inhibitor, was tested to determine whether it could reverse any changes induced by early ethanol exposure. Hence, from P25 to P31, ethanol-exposed male rats were injected with vinpocetine (20mg/kg/day i.p.) or vehicle (DMSO) prior to undergoing behavioral testing in the open field and Morris water maze (MWM) tests. Ethanol exposure did not adversely affect spatial memory in the MWM. A key finding in this study was a significant ethanol-induced change in the function of the phosphorylated extracellular signal-related kinase (P-ERK) signaling pathway in the prefrontal cortex (PFC) and dorsal hippocampus (DH) of rats that did not display overt behavioral deficits. The P-ERK/ERK ratio was decreased in the PFC and increased in the DH of ethanol-exposed rats compared with controls. Rats that received vinpocetine in addition to ethanol did not display any behavioral changes but did show alterations in neural plasticity-related proteins. Mitogen-activated protein kinase phosphatase was increased, whereas brain-derived neurotrophic factor was decreased, in the PFC of vinpocetine-treated ethanol-exposed rats, and phosphorylated-glycogen synthase kinase ? and synaptophysin were increased in the DH of these rats. This study provides insight into the long-term effects of early ethanol exposure and its interaction with vinpocetine in the rat brain.