CRI Newsletter Mar 2003

Exercise & the Brain
The Journal of Neuroscience

Apart from its physical benefits, new findings show that exercise also can boost brain function, tone neural connections, and shape up memory and learning.

One study found that joggers consistently performed better than non-joggers on learning and memory tests that required the use of the prefrontal cortex. This area of the brain is located behind the forehead and is known for its ability to carry out complex functions involving learning and memory.

In the study, Kisou Kubota, MD, and his colleagues at the Nihon Fukushi University in Japan compared seven healthy joggers with seven healthy non-joggers. The joggers ran for 30 minutes, several times a week for 12 weeks. Before and after the training period, the researchers tested prefrontal function with three memory tasks using a computer.

"The tests showed that joggers had a clear improvement in prefrontal function over non-joggers," says Kubota. "These improvements, however, went down when the joggers stopped their training, which suggests that ongoing exercise is required to maintain the benefit."

A key mediator of exercise's effect on learning and memory is brain-derived neurotrophic factor (BDNF), which is a protein known to have a critical role in the repair and maintenance of neural circuits. Fernando Gomez-Pinilla, PhD, and his colleagues at the University of California in Los Angeles, found that voluntary exercise increased levels of BDNF in the hippocampus, a brain area involved with learning and memory.

The researchers found that exercise helped rats overcome poor cognitive function caused by nutritional factors. "A typical diet of most industrialized western societies, high in saturated fat and refined carbohydrates, can contribute to cognitive decline," says Gomez-Pinilla. These new studies suggest that "exercise can be used as a compensatory strategy to ameliorate the effects of an unhealthy diet on both cognition and neural function," he adds.

Researchers at the University of Colorado in Denver, led by David Albeck, PhD, found that even a light exercise routine can create the beneficial BDNF effect in rats. Previous reports showed that rigorous physical exercise, like high-intensity treadmill running, stimulated BDNF expression in the brain. The downside is that sometimes high-intensity workouts can be stressful experiences that increase the release of stress hormones. Stress hormones can suppress BDNF production, thereby canceling the positive effects of the BDNF rise from the exercise.

As a next step, the researchers plan to test whether mild exercise can boost BDNF in aged rats with low BDNF levels. "Aged rats often develop problems with short-term memory processing, similar to symptoms often reported in older people," says Albeck. "Enhancing BDNF expression in the brains of older rats may enhance their memory."

Study is first to confirm link between exercise and changes in brain

Three key areas of the brain adversely affected by aging show the greatest benefit when a person stays physically fit. The proof, scientists say, is visible in the brain scans of 55 volunteers over age 55.

The idea that fitness improves cognition in the aging is not new. Animal studies have found that aerobic exercise boosts cellular and molecular components of the brain, and exercise has improved problem solving and other cognitive abilities in older people. A new study in the February 2003 issue of the Journal of Gerontology: Medical Sciences, however, is the first to show - using high-resolution magnetic resonance imaging - anatomical differences in gray and white matter between physically fit and less fit aging humans.

Gray matter consists of thin layers of tissue of cell bodies such as neurons and support cells that are critically involved in learning and memory. White matter is the myelin sheath containing the nerve fibers that transmit signals throughout the brain.

As people age, especially after age 30, these tissues shrink in a pattern closely matched by declines in cognitive performance, Kramer said.

The authors, led by Arthur F. Kramer of the University of Illinois at Urbana-Champaign, said that the findings "provide the first empirical confirmation of the relationship between cardiovascular fitness and neural degeneration as predicted" in various academic studies on aging and cognition in both animal and human populations.

"We found differences in three areas of the brain, the frontal, temporal and parietal cortexes," Kramer said. "There were very distinct differences particularly in two types of tissue, the gray matter and white matter. Nobody has reported this before."

A second Kramer-led study - a meta-analysis of 18 previous studies - published in March 2003 in Psychological Science, suggests that older women, especially those on hormone replacement therapy, benefit more cognitively than do men from increased physical activity as they age.

The Journal of Gerontology study involved well-educated men and women aged 55-79. Their fitness ranged from sedentary to very fit, competitive-ready athletes. Fitness was measured by results of 1-mile-walking and treadmill stress tests. Three-dimensional scans of the participants' brains were done using MRI equipment at Carle Foundation Hospital in Urbana. Applying voxel-based morphometry, researchers estimated tissue atrophy in a point-by-point fashion in the targeted regions of the brain.

"Interestingly, we found that fitness per se didn't have any influence on brain density," said Kramer, a professor of psychology and member of the Beckman Institute for Advanced Science and Technology at Illinois. "It is fitness as it interacts with age that has the positive effects. Older adults show a real decline in brain density in white and gray areas, but fitness actually slows that decline."

In the study, most other potential negative attributes - smoking, diabetes, drinking, dieting, etc. - were factored out of the data equation, Kramer said.

"This, to our knowledge, is the first human data providing a potential anatomical account of the cognitive effects that we and others have found over the years," Kramer said. "Our data also suggest that more research is clearly needed to actually do a thorough examination of brain structure and functioning, and the impact of interventions such as fitness and cognitive training."

In 1999, Kramer and colleagues reported in the journal Nature that previously sedentary people over age 60 who walked rapidly for 45 minutes three days a week can significantly improve mental processing abilities that decline with age, and particularly tasks that rely heavily on the frontal lobes of the brain.

For their meta-analysis paper, researchers reviewed 18 intervention studies done between 1966 and 2001 and involving hundreds of participants ages 55 and older. Fitness training was found to show "robust but selective benefits for cognition, with the largest fitness-induced benefits occurring for executive-control processes."

Few studies done in the early part of the time included women, but as data were analyzed from later studies, Kramer said, "We found that gender had a large effect; men simply don't benefit as much, so we went back through our own data and asked why."

In previous studies of mice whose ovaries had been removed, they noted a decline in exercise and a drop in production of brain-derived neurotropin. When mice were put back on estrogen, production of the brain molecule increased and so did exercise activity.

In women, Kramer said, the data showed a similar trend: Women on estrogen replacement therapy benefited more than women not on it.

Other main conclusions from the meta-analysis:

* Exercise programs involving both aerobic exercise and strength training produced better results on cognitive abilities than either one alone.

* Older adults benefit more than younger adults do, possibly, Kramer said, because older adults have more to gain as age-related declines become more prevalent.

* More than 30 minutes of exercise per session produces the greatest benefit, a finding consistent with many existing guidelines for adults.

The studies were funded by the National Institute on Aging (National Institutes of Health) and the New York-based Institute for the Study of Aging.

"These intriguing data suggest there may be one more possible benefit from regular exercise," said Molly V. Wagster, program director for the Neuropsychology of Aging, Neuroscience and Neuropsychology of Aging Program of the NIA, which supported the work. "The study emphasizes the importance of continued research on the potential role that exercise might play in reducing cognitive decline with age."

Illinois contributors to the Journal of Gerontology paper were Kramer; postdoctoral researcher Stanley J. Colcombe; doctoral student Kirk I. Erickson; Andrew G. Webb, professor of electrical and computer engineering; Neal Cohen, professor of psychology; and Edward McAuley, professor of kinesiology. Naftali Raz of Wayne State University in Detroit also was a coauthor. Colcombe and Kramer performed the meta-analysis study. This article was prepared by Obesity, Fitness & Wellness Week editors from staff and other reports.

Deficient auditory processing in children with Asperger Syndrome, as indexed by event-related potentials

Eira Jansson-Verkasalo, Rita Ceponienec,Marko Kielinene, Kalervo Suominenb, Ville Jänttib, Sirkka-Liisa Linnae, Irma Moilanene and Risto Näätänenc

Department of Finnish, Saami and Logopedics, University of Oulu, Oulu, Finland
Cognitive Laboratory, Clinical Neurophysiology, Oulu University Hospital,
Cognitive Brain Research Unit, Department of Psychology, University of Helsinki, Finland
Center for Research in Language, University of California, San Diego, CA,

Asperger Syndrome (AS) is characterized by normal language development but deficient understanding and use of the intonation and prosody of speech. While individuals with AS report difficulties in auditory perception, there are no studies addressing auditory processing at the sensory level. In this study, event-related potentials (ERP) were recorded for syllables and tones in children with AS and in their control counterparts. Children with AS displayed abnormalities in transient sound-feature encoding, as indexed by the obligatory ERPs, and in sound discrimination, as indexed by the mismatch negativity. These deficits were more severe for the tone stimuli than for the syllables. These results indicate that auditory sensory processing is deficient in children with AS, and that these deficits might be implicated in the perceptual problems encountered by children with AS.

Musicians' Brains Are Different

Are the people who perform great music written by Mozart, Handel and Bach really different? New research suggests that they are. The brain waves of professional musicians respond to music in a way that suggests they possess an intuitive sense of the notes that amateurs lack.

In studies of eight professional violinists with German orchestras and eight amateur violinists, researchers at the University of Tuebingen found that professionals had significant activity in the part of the brain that controls hearing.

In one experiment, the scientists used functional magnetic resonance imaging (fMRI), which detects changes in blood flow to particular areas of the brain, to scan the brains of eight professional musicians and eight amateur musicians while they executed the fingering used to play a musical piece. Each of the study participants performed the fingering of the first 16 bars of Mozart's violin concerto in G major. This concerto was chosen because it is part of the repertoire of professional violinists and not difficult for amateurs to play.

Gabriela Scheler, PhD, the primary investigator on the study, is a former violinist with the Nuremberg Philharmonic Orchestra. She found that "Activity in the motor cortex, the part of the brain that controls finger movements, was much more economic and focused in the brains of the professional musicians." This suggests that professional musicians who have practiced the concerto so many times use their brains more efficiently, because the playing has become automatic.

The auditory region of the brain, however, showed heightened activity with the professionals and less activity for the amateurs. "When the professionals move their fingers they are also hearing the music in their heads, so that's why the auditory region is more active," says Scheler. "Presumably, this enhances the musical performance."

In a second experiment, both groups of musicians were told to imagine playing the concerto without moving their fingers to find out if the same neuronal networks are activated while executing the movements. Once again, the professionals showed more focused activity in the motor cortex and increased activity in the auditory region.

"Our next step is to observe brain activity in people before and after they've been trained to imagine the performance of a piece of music," says Scheler. "We will look to see if imagery training changes brain activity and if it improves performance."

Dissecting the circuitry of the auditory system
George D. Pollak, R. Michael Burger and Achim Klug

Section of Neurobiology, The University of Texas at Austin,
Virginia Merrill Bloedel Hearing Research Center,
University of Washington, Seattle, WA
Oregon Hearing Research Center, Oregon Health Sciences University of Portland, OR

The brainstem auditory system is a complex system composed of numerous parallel and serial pathways that converge on a common destination in the inferior colliculus (IC). The exact nature of the response transformations that occur in the IC have, however, been elusive – even though the IC has been the subject of numerous studies for more than 30 years. Recent studies have addressed this issue by recording from IC neurons before and during micro-iontophoresis of drugs that selectively block GABAA or glycine receptors (the dominant inhibitory receptors in the IC) or by reversibly inactivating a lower nucleus that provides inhibitory innervation to the IC. These studies have revealed some of the ways that signals, relayed via many different parallel routes, interact in the IC, and suggest some functional advantages that these interactions might have.

Two of the primary goals of auditory neuroscience are to determine how acoustic information is progressively transformed along the auditory pathway and to understand the functional consequences of those transformations. These goals have been difficult to achieve, in large part owing to the complexity of the auditory system. The ascending auditory system is composed of a large number of nuclei connected through a series of parallel pathways. The pathways begin with the auditory nerve, which branches to distribute information to the various cell groups in the cochlear nucleus (Fig. 1). Each cell group in the cochlear nucleus transforms the incoming spike trains uniquely [1] and then distributes that information along a series of parallel pathways to a myriad of auditory nuclei in the medulla and pons. Some of these nuclei are binaural, receiving innervation from the cochlear nuclei on both sides, whereas others are innervated from the cochlear nucleus on only one side and are monaural. The outputs from all of these binaural and monaural nuclei then converge on the inferior colliculus (IC) in the midbrain [2, 3 and 4]. The IC provides the principal source of innervation to the medial geniculate body [5 and 6] and, thus, indirectly to the auditory cortex ( Fig. 1). Therefore, the IC is the nexus of the auditory system because it processes and integrates almost all ascending acoustic information from lower centers, and determines the form in which information is conveyed to higher regions in the forebrain.

Major connections of the ascending auditory system, showing the enormous convergence of projections onto the inferior colliculus from the majority of lower nuclei. Excitatory projections are shown as black lines and inhibitory projections are shown as red lines (GABAergic projections) or green lines (glycinergic projections). One of the parallel projections from the cochlear nucleus innervates the principal cell groups in the superior olivary complex: the medial nucleus of the trapezoid body (MNTB), and two binaural nuclei, the lateral superior olive (LSO) and the medial superior olive (MSO). The three principal nuclei of the lateral lemniscus (dorsal, ventral and intermediate) are situated rostral to the superior olive and just below the inferior colliculus. The ventral and intermediate nuclei receive innervation from only one ear and are, therefore, monaural; the dorsal nucleus of the lateral lemniscus receives innervation from both ears and is binaural. The dorsal nucleus is also GABAergic and provides strong inhibitory innervation to the inferior colliculus bilaterally and to the opposite dorsal nucleus via a commissural projection.

Although the IC has been intensively studied, it remains an enigma. On the one hand, the response properties of IC neurons evoked by tones, noise or other conventional signals are, with only a few exceptions, very similar to the properties of neurons in one or another of the lower nuclei from which IC cells receive their innervation. Such results were obtained in a variety of mammals, including echolocating bats. These similarities have led some investigators to the viewpoint that the major processing occurs in lower nuclei and that IC response properties are, for the most part, a reflection of the particular lower nuclei that innervate the IC cell in question. On the other hand, substantial changes in most response properties occur when inhibitory inputs to the IC are blocked. These results have led to an alternative viewpoint, which holds that the enormous convergence of excitatory and inhibitory inputs produces a corresponding degree of processing and, hence, substantial transformations of response features. As explained below, both viewpoints receive support from recent studies.

1. IC neurons and lower auditory nuclei often have similar response properties

Similar response properties in IC and lower nuclei are well illustrated by neurons that are excited by stimulation of one ear and inhibited by stimulation of the other ear (EI neurons). These neurons encode interaural intensity disparities (IIDs), the principal cues animals use to localize high frequency sounds. EI properties are revealed by simply presenting a sound of fixed intensity to the excitatory ear and simultaneously presenting sounds of progressively increasing intensity to the opposite or inhibitory ear. The sound at the excitatory ear drives the neuron and this driven activity is progressively inhibited by increasing the intensity at the inhibitory ear. The feature we focus on is the smallest IID (the IID with the lowest intensity at the inhibitory ear) that evokes maximal spike suppression in each EI neuron, termed the IID of maximal inhibition (IIDmi) of the neuron.

The principal brainstem nuclei devoted to processing interaural intensity disparities (IIDs) are the lateral superior olive (LSO), the dorsal nucleus of the lateral lemniscus (DNLL) and the inferior colliculus (IC). The intensities received at the two ears are first processed binaurally in the LSO. The coded intensities are compared by subtraction, whereby the coded intensity from the ipsilateral ear excites each LSO neuron and the coded intensity from the contralateral ear inhibits each LSO neuron via glycinergic neurons from the medial nucleus of the trapezoid body (MNTB). EI properties (the ability to be excited by stimulation of one ear and inhibited by stimulation of the other ear) are studied by presenting a sound of fixed intensity to the excitatory ear to drive neuronal firing, and then documenting how progressively increasing sound intensity at the inhibitory ear reduces the discharges evoked by the sound at the excitatory ear. Because the excitatory intensity is fixed, each change in the inhibitory intensity generates a different IID. The IID function for each neuron plots these changes in spike count with IID, and the lowest IID that causes maximal suppression is the IIDmi of the neuron (arrows in plots of IIDs shown for the LSO). The IID functions of several LSO neurons are shown, to illustrate the range of IIDmi expressed by the LSO population. Virtually the same IID functions and range of IIDmi occur in the LSO, the DNLL ipsilateral to the excitatory input, and in the population of EI neurons in the IC contralateral to the excitatory input. The IID functions for the left DNLL are inverted versions of those of the left LSO and right IC because the DNLL on that side is inhibited by sound at the left ear and excited by sound at the right ear. Although the IID functions of IC cells are similar to those of LSO and DNLL cells, EI cells in the IC receive a large innervation from the LSO bilaterally, from the DNLL bilaterally, and from lower monaural nuclei, as illustrated by the projection from the cochlear nucleus. Abbreviations: INLL, intermediate nucleus of the lateral lemniscus; VNLL, ventral nucleus of the lateral lemniscus.

Neurons initially acquire EI properties in the lateral superior olive (LSO). However, EI neurons are also prevalent in auditory nuclei above the LSO, especially in the dorsal nucleus of the lateral lemniscus (DNLL), a purely GABAergic nucleus that projects bilaterally to the IC. Additionally, EI cells dominate portions of the IC that receive innervation from the LSO and DNLL. Because the LSO sends strong, excitatory projections to both the opposite DNLL and opposite IC, it could be that the EI properties created in the LSO are simply imposed on their targets in the DNLL and IC. Indeed, many EI cells in the IC seem to be formed in this way, which supports the view that IC neurons reflect properties that were created in a lower nucleus, presumably the LSO

Some principal connections from lower nuclei to EI neurons (neurons that are excited by stimulation of one ear and inhibited by stimulation of the other ear) in the inferior colliculus (IC) (a) and the various ways in which EI properties can be formed by subsets of those projections (b–d). The dorsal nucleus of the lateral lemniscus (DNLL, shown in red) is a purely GABAergic nucleus that provides strong inhibitory projections to both the ipsilateral and contralateral IC. Excitatory projections are shown as solid black lines and inhibitory projections as colored lines. The interaural intensity disparity (IID) function of an IC neuron is first evaluated by monitoring discharges in response to binaural stimulation using the recording barrel of a multi-barrel pipette (a). Bicuculline (an antagonist of GABAA receptors) or a combination of bicuculline and strychnine (an antagonist of glycine receptors) can be iontophoretically applied to an IC neuron, thereby blocking inhibition at the IC. Alternatively, the DNLL is reversibly inactivated by iontophoresis of kynurenic acid, a broad-spectrum blocker of glutamate receptors (b–d). IID function obtained before blocking inhibition is shown as dashed black lines and IID functions obtained after blocking inhibition are solid green lines. (b) Circuit showing how EI properties, which are first formed in the lateral superior olive (LSO), are imposed on the IC cell through a strong crossed excitatory projection. The IID functions of these IC cells are unchanged when inhibition is blocked at the IC or when the DNLL is reversibly inactivated. (c) Circuit showing how EI properties, which are first formed in the LSO, can be modified in the IC through the convergence of LSO and DNLL projections. The net effect of this convergence is to create EI cells in the IC that are suppressed by lower intensities at the ipsilateral ear than they would be if they received only the LSO projection (their IIDmi are shifted to the right when inhibition is blocked). The IID function obtained after blocking inhibition (solid green line) presumably reflects the IID function of the LSO projection. (d) Circuit showing how EI properties can be formed de novo in the IC. Stimulation of the ear contralateral to the IC (left ear) drives a lower monaural nucleus, shown generically here as the cochlear nucleus, which provides the excitation to the IC cell. Stimulation of the ear ipsilateral to the IC (right ear) excites the DNLL, which then provides the inhibition that suppresses the excitation in the IC evoked by stimulation of the left, excitatory ear. Blocking inhibition at the IC, or reversibly inactivating the DNLL with kynurenic acid, abolishes the inhibition evoked by the ipsilateral (right) ear and transforms what was previously a strongly inhibited EI cell into one that is monaural and influenced only by excitation evoked by stimulation of the left ear.

2. EI neurons are formed in multiple ways in the IC

Subjecting IC neurons to more challenging tests, however, reveals that the EI properties of many IC cells are not simply a reflection of LSO projections. The first question these tests were designed to answer is simple: does the actual inhibition evoked by stimulation of the inhibitory ear occur in the IC or does it occur in a lower nucleus, presumably the LSO? If the inhibition occurs in the LSO, then blocking inhibition at the IC cell should have no effect on ipsilaterally evoked inhibition; the IC cell should be EI whether or not that inhibition is blocked at the IC . If, however, EI properties are completely or partially created in the IC through inhibitory projections from lower nuclei, then blocking inhibition at the IC should substantially reduce ipsilaterally evoked inhibition, or even abolish it completely. By evaluating the IC in this way, studies from several laboratories showed that the EI properties in the majority of IC cells are either modified or created de novo in the IC through a GABAergic inhibitory projection. Moreover, by reversibly inactivating the opposite DNLL while recording from EI neurons in the IC, several studies in rats and bats showed that the source of the GABAergic inhibition is the contralateral DNLL. The effects of blocking inhibition are continuous, and range from no effect in some neurons, to shifts in the IIDmi (the most common modification of EI properties), to a complete or nearly complete elimination of inhibition – thereby transforming the neuron from one that was EI into a monaural neuron, which is only influenced by sound presented to one ear.

These data support the view that the IC is a center for integration and transformation but they also raise several questions. For example, why do the IIDmi of some IC cells have to be modified from circuit interactions? The populations of LSO and IC neurons express a similar range of IIDmi, although the LSO population emphasizes IIDmi of ~0 dB, whereas the IC population emphasizes larger IIDmi. If the primary function of ipsilaterally evoked inhibition at the IC is to shift the IIDmi of some IC cells, it would seem more economical for the axons of LSO cells possessing the required IIDmi simply to branch more profusely to innervate a larger number of IC cells than LSO cells with other IIDmi. Such a differential innervation would create a population of IC cells that has the same range of IIDmi as the LSO population, but that would also have the expanded representation of larger IIDmi found in the EI population of the IC. An even more perplexing question is: what is the functional significance of recreating EI properties de novo in the IC when EI cells have already been created in abundance in the LSO? One insight into this question is provided by a unique feature of inhibition at the DNLL, as explained in the following section.

3. Properties of DNLL neurons predict emergent properties of some EI neurons in the IC

The DNLL, like the IC, receives a large complement of inputs from lower nuclei and the neurons within it that are tuned to high frequencies are predominately, if not exclusively, EI . Stimulation of the contralateral (excitatory) ear typically evokes a strong, sustained discharge train. The duration of the discharge train corresponds to the duration of the stimulus, and is never longer. By contrast, stimulation of the ipsilateral (inhibitory) ear evokes a long-lasting inhibition that persists for periods ranging 5–80 ms longer than the duration of the signals that generated it. The average duration of the persistent inhibition is ~18 ms. In other words, the DNLL remembers that a stimulus was received at the ipsilateral ear for ~18 ms, on average, after the stimulus has ended.

Circuitry that creates EI properties (the ability to be excited by stimulation of one ear and inhibited by stimulation of the other ear) in neurons of the dorsal nucleus of the lateral lemniscus (DNLL). (a) Binaural signals that favor the contralateral (right) ear excite neurons in the lateral superior olive (LSO) that then excite DNLL neurons through a crossed excitatory projection. Each sound evokes a sustained discharge train in DNLL neurons with a duration equal to that of the stimulus (tone burst) duration. (b) Binaural signals that favor the ipsilateral (left) ear inhibit DNLL neurons. The inhibition is evoked through the LSO on the same (left) side. This LSO provides a strong glycinergic projection to the DNLL, but the same LSO excites the opposite DNLL. The opposite (right) DNLL sends a strong GABAergic projection through the commissure of Probst to inhibit the DNLL on the other (left) side. The noteworthy feature of the inhibition at the DNLL is that the resulting inhibition lasts substantially longer (on average ~18 ms longer) than the signal that generated it.

The persistent inhibition evoked by ipsilateral stimulation is potent and prevents DNLL neurons from responding to signals received at the excitatory (contralateral) ear for a period of time following the inhibitory signal [13, 49 and 50]. Thus, the reception of an initial signal having an IID that favors the inhibitory ear functionally inactivates (persistently inhibits) the DNLL for a period of time. Because many IC cells derive their inhibition from the DNLL, during the period of persistent inhibition of the DNLL these IC cells are deprived of their inhibitory innervation and, thus, are temporarily transformed from strongly inhibited EI cells into weakly inhibited EI, or even monaural, cells [13].

These features suggest that the circuitry linking the DNLL with the IC is important for processing signals which generate IIDs that change over time, such as the IIDs that would be generated by moving stimuli or by multiple sound sources that emanate from different regions of space. The hypothesis predicts that when two sounds with different IIDs are presented in close temporal sequence, there should be a change in the responsiveness of an IC cell to the trailing sound – a change produced by the reception of an earlier sound whose IID is strongly excitatory to the IC cell and inhibitory to the opposite DNLL. Stated differently, the reception of the first sound persistently inhibits the DNLL, thereby depriving the IC of its inhibitory input from the ipsilateral ear. Thus, when a trailing signal with an IID that would normally inhibit the IC cell is received, that signal excites the IC cell because the IC cell is deprived of its inhibitory input from the DNLL at that time. Conversely, the hypothesis also predicts that the responses to a trailing sound should be unchanged by an initial sound in IC neurons that are not innervated by the DNLL.

How a binaural signal having an interaural intensity disparity (IID) that favors the ear contralateral to the inferior colliculus (IC) could reconfigure the circuit and, thus, allow the IC cell to respond to a trailing binaural signal to which it was unresponsive when the trailing signal was presented alone. (a) A binaural signal with an IID that favors the right ear (R), ipsilateral to the IC, drives two projections. The first is a GABAergic inhibitory projection from the opposite (left) dorsal nucleus of the lateral lemniscus (DNLL), which is strongly driven; the second an excitatory projection from a lower monaural nucleus (e.g. the cochlear nucleus), which is not as strongly driven. At this IID, the inhibitory projection from the left DNLL suppresses the excitation at the IC evoked by the weaker stimulation at the left (L), contralateral ear, so there is no overall response. (b) A binaural signal that favors the left, contralateral ear evokes a persistent inhibition in the DNLL (indicated by paler coloring), and the signal excites the right, contralateral IC. Inhibition at the DNLL is evoked by a glycinergic projection from the ipsilateral LSO and GABAergic inhibition from the opposite DNLL, as shown in Fig. 4. The excitation of the IC is through an excitatory projection from a lower monaural nucleus, shown here generically as coming from the cochlear nucleus. (c) The initial presentation of this binaural signal persistently inhibits the DNLL (indicated by paler coloring) but excites the IC, in the same way as shown in (b). When a trailing, binaural signal that favors the right (inhibitory) ear follows shortly thereafter, the IC neuron now responds to the trailing signal. The reason is that the first binaural signal generates persistent inhibition in the DNLL that deprives the IC cell of the inhibition that would be evoked by the trailing binaural signal if the trailing signal were presented alone. Thus, the weaker stimulus at the contralateral (left) ear evoked by the trailing signal is now free to drive the IC cell. (d) For IC neurons that are not innervated by the DNLL, initial signals do not change responses evoked by trailing signals. Whether the binaural signal is presented alone as in (a) or follows an initial signal as in (d), these neurons respond in virtually the same way to that binaural signal.

We tested and confirmed this hypothesis by presenting an initial and trailing sound while recording from IC cells in bats before and during reversible inactivation of the DNLL . In many IC cells, the reception of an initial signal `reconfigured the circuit' by persistently inhibiting the DNLL, thereby allowing the IC cell to respond to a trailing signal – a signal that inhibited the IC cell when presented by itself. In these cells, inactivating the DNLL by iontophoretic application of kynurenic acid (a broad spectrum blocker of glutamate-mediated transmission) relieved inhibition, and transformed that IC cell from one that was EI when the DNLL was functional into one that was monaural when the DNLL was inactivated. The reversible inactivation showed that the EI properties of these cells were created de novo in the IC, and that the DNLL provided the ipsilaterally evoked inhibition. In other IC cells, however, the initial signals had no effects on the responses evoked by the trailing signals; these cells responded to trailing signals as they did when the trailing signals were presented alone. Reversible inactivation of the DNLL had no influence on the EI properties of these cells, suggesting that the EI properties of these cells were formed in the LSO and imposed on their IC targets through an excitatory projection. Thus, the predictions of the hypothesis were confirmed both for IC cells that were innervated by the opposite DNLL and for EI cells that were not innervated by the opposite DNLL.

4. Functional relevance of emergent properties resulting from DNLL innervation

The demonstration that an initial signal can change the responsiveness of IC cells to a trailing signal suggests that the DNLL circuitry could contribute to a precedence-like effect. The precedence effect, or law of the first wavefront, was discovered in human psychophysical studies and is due to a mechanism that suppresses the directional information carried by echoes. It explains how, in a reverberant room, a listener can localize only the first sound and not the sequence of echoes reflected from the various surfaces and objects in the room. Precedence is classically demonstrated with two speakers, separated along the same plane in space. The speakers emit identical sounds but the sound from one speaker is presented a few milliseconds before the sound from the other speaker. Listeners hear a single composite sound, and perceive the composite sound as originating from the leading speaker. The second sound fuses with the first and contributes to the overall volume and timbre of the fused sound, but is not perceived as a separate sound nor does it influence the perceived location of the composite sound. If the interval between the first and second sounds exceeds an upper limit, the two sounds are no longer heard as a single sound but as two separate sounds in succession, each with a perceived location in space.

It is noteworthy that precedence is a widespread, if not universal, feature of auditory systems. Precedence has been found in insects, birds [55] and a variety of mammals. The effect is presumably a manifestation of mechanisms that could enhance the ability of an animal to focus on the primary or first sound in the midst of many sounds. Focus is achieved by localizing only the first sound and merging the percept of the first and trailing sounds, whereas sounds from other sources that are received after a certain interval would be resolved and localized.

The features of IC neurons produced by innervation from the DNLL described above could contribute to precedence. The argument is that the IIDs generated by a sound from a particular location generate a population response in which some cells are excited while others are inhibited. Presumably this population response is interpreted by the brain as a sound that came from a unique location. However, a trailing sound that emanates from a different location would generate a distorted population response that cannot be associated with a location. The distorted population response is evoked by the trailing sound because many EI cells that should be inhibited by that sound are, instead, excited by the trailing sound, owing to the persistent inhibition at the DNLL produced by the initial sound.

5. Concluding comments

The circuitry linking the LSO, DNLL and IC can serve as a model for a more general understanding of how the integration of incoming information creates complex, but biologically meaningful, properties within the IC. Although the variety of response transformations that occur in the IC is far larger than described here for EI cells, we now have a better understanding of roles played by innervation from the DNLL for binaural processing. The significance of this is that it creates emergent properties in the IC, properties that are not possessed by LSO neurons or by IC cells that are not innervated by the DNLL. One property, but probably not the only one, is a change in the binaural responsiveness of the IC cell – a change produced by the reception of an earlier sound, the IID of which is strongly excitatory to the IC cell. Additionally, this emergent property occurs not only in de novo IC cells but also in all IC cells that have binaural properties shaped by projections from the DNLL.

Previously, we raised the question of why the shifts in IIDmi were constructed through circuit interactions rather than an exuberance of axonal branches from LSO cells with positive IIDmi. One dividend of constructing IC cells with inhibition from the DNLL, including those with shifted IIDmi, is that those cells would also express the emergent property described earlier in this review – a property they would not possess if their IIDmi were entirely imposed upon them from LSO projections or were constructed from ipsilateral inhibitory projections from other sources.

We thank Eric Bauer for his helpful comments. Our work is supported by NIH grant DC 00268.