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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    549—Auditory System: Adaptation, Learning, and Memory

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    549.13: Enhanced but dysregulated experience-dependent plasticity in the aged brain due to reduced inhibition

    Location: Halls B-H

    *M. CISNEROS-FRANCO1, E. DE VILLERS-SIDANI2;
    1McGill Univ. Integrated Program In Neurosci., Montreal, QC, Canada; 2Montreal Neurolog. Inst., Montreal, QC, Canada

    Abstract Body: During an early developmental period also known as the “critical period” (CP), cortical inhibitory networks are immature and passive exposures to environmental sounds readily shape the frequency tuning map of the primary auditory cortex (A1) (de Villers-Sidani et al., 2007). Maturation of cortical inhibition ultimately closes the CP, and early experience-dependent alterations in A1 tuning become consolidated and resistant to passive sound exposures. Moreover, a minimum inhibitory tone is necessary for the maintenance of this representational stability in the adult cortex (Pizzorusso et al., 2002).
    In aged rats and humans, although learning is still possible, the process is usually slower and effects short-lived (Boyke et al., 2008; de Villers-Sidani et al., 2010). Notably, the inhibitory elements that are associated with the regulation of plasticity during early development are reduced in the aged brain (Caspary et al., 2008). This altered milieu could result in a progressive increase in representational instability in the aged A1, potentially contributing to the reduced effectiveness of learning in older individuals. Here we tested this hypothesis by comparing the effect of a short passive tone exposure on A1 frequency representation in young adult and aged rats. We found that such exposure resulted in a significant distortion of A1 frequency tuning in the older but not in the younger group. Additionally we found that such distortions could readily be erased by a subsequent exposure to a different tone. Finally we administered the GABA-A potentiator diazepam in the aged group during the exposure and found that it made A1 once again resistant to passive alterations in frequency tuning.
    Our findings show that experience-dependent plasticity is paradoxically enhanced but dysregulated in the aging brain likely due due to an age-related reduction in inhibition. Such instability could have a direct negative impact on the acquisition and persistence of learning in the aged brain.

    Lay Language Summary: Our research shows that the aging brain is surprisingly more plastic than the young adult brain –it has a greater ability to change as a result of experience. By means of altering the auditory environment of aging rats, we found that these experience-driven changes were unstable: both easy to achieve and easy to reverse. Moreover, we show that enhancing brain inhibition can reduce this instability. These results provide novel insights into the rules of plasticity in the aging brain, which could potentially inform the development of new strategies to harness its full plastic potential.
    We are able to understand and interact with the world around us because our brain creates sensory representations or maps of our environment. One of such maps is “the A1 frequency tuning map”, where neurons are “tuned” to detect specific sound frequencies. Early in life, simple passive exposure of developing rats to a single tone during a few days results in quasi-permanent over-representation of that exposure tone; that is, a greater number of neurons become tuned to that tone. As the brain matures the adult A1 progressively becomes resistant to such passive exposures, and A1 plasticity is seen almost exclusively in the context of auditory training. This transition from largely unregulated plasticity to tightly regulated plasticity is important to make sound processing reliable and prevent the loss of fundamental skills acquired during early development. Everything points toward a progressive increase in brain inhibition during development as the primary brain mechanism responsible for this transition. Interestingly, brain aging is associated with a progressive loss of inhibition. A widely accepted notion is that the aging brain has a reduced plasticity, as older individuals tend to recover less than younger one from a neurological injury such as a stroke. However, as we show below, this notion is unlikely to be correct in detail, as the aged brain is in some ways more plastic than the young brain. Instead, we propose that the regulation of plasticity, rather than plasticity per se, is altered in the aging brain.
    To test this hypothesis, we first exposed aged rats to a repetitive tone continuously for one week and we found that passive sound exposure resulted in an over-representation of the exposure tone in aged rats as is seen in very young rats. As expected, this exposure had no impact in young adults. This shows that the aging A1 is, in an unexpected way, more plastic than the young but mature A1. To document further the extent of this A1 instability we examined in another group of older adults the effect of an exposure to a different tone during a second week of exposure. In that group we found that the effect of the first tone had almost entirely vanished at the end of the second week: now instead the second exposure tone was clearly over-represented in A1. We then examined the effect of enhancing brain inhibition in aged rats on A1 tuning stability. To do so, we exposed older rats sequentially to two tones as previously but this time gave them throughout the exposure a small dose of diazepam, a drug that boosts brain inhibition. After the end of the two weeks, A1 tuning had this time crystallized around the exposure tone of the first week instead of the second, suggesting that map instability was greatly reduced.
    We show that A1 plasticity is enhanced but dysregulated in the aged brain, likely due to reduced inhibition. Such instability could potentially have negative consequences for learning and neurological recovery in older individuals by permitting a continuous decay of gains made through training or rehabilitation.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    549—Auditory System: Adaptation, Learning, and Memory

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    549.13: Enhanced but dysregulated experience-dependent plasticity in the aged brain due to reduced inhibition

    Location: Halls B-H

    *M. CISNEROS-FRANCO1, E. DE VILLERS-SIDANI2;
    1McGill Univ. Integrated Program In Neurosci., Montreal, QC, Canada; 2Montreal Neurolog. Inst., Montreal, QC, Canada

    Abstract Body: During an early developmental period also known as the “critical period” (CP), cortical inhibitory networks are immature and passive exposures to environmental sounds readily shape the frequency tuning map of the primary auditory cortex (A1) (de Villers-Sidani et al., 2007). Maturation of cortical inhibition ultimately closes the CP, and early experience-dependent alterations in A1 tuning become consolidated and resistant to passive sound exposures. Moreover, a minimum inhibitory tone is necessary for the maintenance of this representational stability in the adult cortex (Pizzorusso et al., 2002).
    In aged rats and humans, although learning is still possible, the process is usually slower and effects short-lived (Boyke et al., 2008; de Villers-Sidani et al., 2010). Notably, the inhibitory elements that are associated with the regulation of plasticity during early development are reduced in the aged brain (Caspary et al., 2008). This altered milieu could result in a progressive increase in representational instability in the aged A1, potentially contributing to the reduced effectiveness of learning in older individuals. Here we tested this hypothesis by comparing the effect of a short passive tone exposure on A1 frequency representation in young adult and aged rats. We found that such exposure resulted in a significant distortion of A1 frequency tuning in the older but not in the younger group. Additionally we found that such distortions could readily be erased by a subsequent exposure to a different tone. Finally we administered the GABA-A potentiator diazepam in the aged group during the exposure and found that it made A1 once again resistant to passive alterations in frequency tuning.
    Our findings show that experience-dependent plasticity is paradoxically enhanced but dysregulated in the aging brain likely due due to an age-related reduction in inhibition. Such instability could have a direct negative impact on the acquisition and persistence of learning in the aged brain.

    Lay Language Summary: Our research shows that the aging brain is surprisingly more plastic than the young adult brain –it has a greater ability to change as a result of experience. By means of altering the auditory environment of aging rats, we found that these experience-driven changes were unstable: both easy to achieve and easy to reverse. Moreover, we show that enhancing brain inhibition can reduce this instability. These results provide novel insights into the rules of plasticity in the aging brain, which could potentially inform the development of new strategies to harness its full plastic potential.
    We are able to understand and interact with the world around us because our brain creates sensory representations or maps of our environment. One of such maps is “the A1 frequency tuning map”, where neurons are “tuned” to detect specific sound frequencies. Early in life, simple passive exposure of developing rats to a single tone during a few days results in quasi-permanent over-representation of that exposure tone; that is, a greater number of neurons become tuned to that tone. As the brain matures the adult A1 progressively becomes resistant to such passive exposures, and A1 plasticity is seen almost exclusively in the context of auditory training. This transition from largely unregulated plasticity to tightly regulated plasticity is important to make sound processing reliable and prevent the loss of fundamental skills acquired during early development. Everything points toward a progressive increase in brain inhibition during development as the primary brain mechanism responsible for this transition. Interestingly, brain aging is associated with a progressive loss of inhibition. A widely accepted notion is that the aging brain has a reduced plasticity, as older individuals tend to recover less than younger one from a neurological injury such as a stroke. However, as we show below, this notion is unlikely to be correct in detail, as the aged brain is in some ways more plastic than the young brain. Instead, we propose that the regulation of plasticity, rather than plasticity per se, is altered in the aging brain.
    To test this hypothesis, we first exposed aged rats to a repetitive tone continuously for one week and we found that passive sound exposure resulted in an over-representation of the exposure tone in aged rats as is seen in very young rats. As expected, this exposure had no impact in young adults. This shows that the aging A1 is, in an unexpected way, more plastic than the young but mature A1. To document further the extent of this A1 instability we examined in another group of older adults the effect of an exposure to a different tone during a second week of exposure. In that group we found that the effect of the first tone had almost entirely vanished at the end of the second week: now instead the second exposure tone was clearly over-represented in A1. We then examined the effect of enhancing brain inhibition in aged rats on A1 tuning stability. To do so, we exposed older rats sequentially to two tones as previously but this time gave them throughout the exposure a small dose of diazepam, a drug that boosts brain inhibition. After the end of the two weeks, A1 tuning had this time crystallized around the exposure tone of the first week instead of the second, suggesting that map instability was greatly reduced.
    We show that A1 plasticity is enhanced but dysregulated in the aged brain, likely due to reduced inhibition. Such instability could potentially have negative consequences for learning and neurological recovery in older individuals by permitting a continuous decay of gains made through training or rehabilitation.