Mechanisms for acute changes in sensory maps

Many studies have examined changes in the topographic representations of the special senses in cerebral cortex following partial peripheral deafferentations. This approach has demonstrated the short- medium- and long-term aspects of plasticity. However, the extensive capacity for immediate plasticity, while first demonstrated more than 15 years ago, still challenges explanation. What such studies indicate is that each locus in sensory cortex receives viable input from a far wider area of the sensory epithelium than is represented in the normal receptive field, with the implication that much of this input is normally inhibited. Consideration of the geometric and temporal aspects of receptive field plasticity suggests that this inhibition must be tonic and must derive its driving input from a tonically active periphery

Pregnane steroids and short-term neural plasticity

Gamma-aminobutyric acid (GABA) is the major inhibitory transmitter in the brain, and its fast effects are mediated by the GABA-A receptor. It is well known, from pharmacological manipulations, that many exogenous agents alter the efficacy of GABA-A receptors. For example, benzodiazepines increase the effect of GABA and some β-carbolines reduce the effect of GABA at these receptors. Increasing the strength of neuronal inhibition can prevent seizures, reduce anxiety and be neuroprotective. There are also endogenous mechanisms that increase efficacy. For example, more GABA-A receptors can be synthesized and inserted into synapses, but this requires up to 1 h or more. On a shorter timescale, GABAergic inhibition can be potentiated by steroids, e.g., allopregnanolone, synthesized de novo in neural tissue or derived from peripheral endocrine organs. The widespread distribution of these neuroactive steroids across the brain suggests an extensive role in short-term neural plasticity

Neurosteroids mediate habituation and tonic inhibition in the auditory midbrain

Habituation of the behavioral response to a repetitive stimulus is a well-established observation in perceptual studies and is considered a basic form of nonassociative learning. There is also a long history of physiological studies suggesting that central nervous system habituation is mediated by inhibition. At higher levels of the sensory pathways, such inhibition is mainly contributed by GABAa receptor mechanisms. Concepts of modification of synaptic efficacy that apply to excitatory amino acid synaptic transmission do not have direct parallels with these inhibitory synapses: quantal release of GABA rapidly saturates available receptors at a synapse, placing an upper limit on responsiveness to increased transmitter release. However, pharmacological modulation of GABAa-receptor efficacy with exogenous agents (e.g., benzodiazepines and β-carbolines) is known to occur through allosteric mechanisms that modulate the effectiveness (positive and negative) of GABA at this receptor. The most potent endogenous modulators are 5α-reduced steroids, Production of these steroids was attenuated in adult rats with systemic injection of Finasteride, a competitive substrate for 5α-reductase. This treatment was sufficient to block habituation of the evoked midbrain response to repetitive presentation of an acoustic click. This result confirms that simple habituation is due to an increase in active inhibition, the increase being mediated by steroid modulation of the GABAa-receptor. Finasteride treatment also brought about a 23% increase in the evoked response to a click stimulus, suggesting that 5α-reduced steroids normally contribute to tonic inhibition in the rat inferior colliculus

Neurosteroids involved in regulating inhibition in the inferior colliculus.

Fast inhibitory neurotransmission in the brain is largely mediated by the gamma-aminobutyric acid-type A (GABA(A)) receptor. The 3alpha,5alpha-reduced neurosteroids (e.g., allopregnanolone) are the most potent endogenous modulators of the GABA(A) receptor. Although it is known that 3alpha,5alpha-reduced neurosteroid levels change during stress or depression and over the estrus cycle, a basic physiological role consistent with their pharmacological action remains elusive. We used the unique architecture of the auditory midbrain to reveal a role for 3alpha,5alpha-reduced neurosteroids in regulating inhibitory efficacy. After blocking the massive GABAergic projection from the dorsal nucleus of the lateral lemniscus (DNLL) to the contralateral central nucleus of the inferior colliculus (ICC) in anesthetized rats, a reactive increase in the efficacy of other inhibitory circuits in the ICC (separable because of the dominant ear that drives each circuit) was demonstrated with physiological measures-single-neuron activity and a neural-population-evoked response. This effect was prevented by blocking 3alpha,5alpha-reduced neurosteroid synthesis with a 5alpha-reductase inhibitor: finasteride. Immunohistochemistry confirmed that the DNLL blockade induced an increase in 3alpha,5alpha-reduced neurosteroids in the contralateral ICC. This study shows that when GABAergic inhibition is reduced, the brain compensates within minutes by locally increasing synthesis of neurosteroids, thereby balancing excitatory and inhibitory inputs in complex neural circuits