Eric I. Knudsen

Sensitive Periods in the Development of the Brain and Behavior

Experience exerts a profound influence on the brain and, therefore, on behavior. When the effect of experience on the brain is particularly strong during a limited period in development, this period is referred to as a sensitive period. Such periods allow experience to instruct neural circuits to process or represent information in a way that is adaptive for the individual. When experience provides information that is essential for normal development and alters performance permanently, such sensitive periods are referred to as critical periods. Although sensitive periods are reflected in behavior, they are actually a property of neural circuits. Mechanisms of plasticity at the circuit level are discussed that have been shown to operate during sensitive periods. A hypothesis is proposed that experience during a sensitive period modifies the architecture of a circuit in fundamental ways, causing certain patterns of connectivity to become highly stable and, therefore, energetically preferred. Plasticity that occurs beyond the end of a sensitive period, which is substantial in many circuits, alters connectivity patterns within the architectural constraints established during the sensitive period. Preferences in a circuit that result from experience during sensitive periods are illustrated graphically as changes in a stability landscape, a metaphor that represents the relative contributions of genetic and experiential influences in shaping the information processing capabilities of a neural circuit. By understanding sensitive periods at the circuit level, as well as understanding the relationship between circuit properties and behavior, we gain a deeper insight into the critical role that experience plays in shaping the development of the brain and behavior.

Mechanisms of sound localization in the barn owl (Tyto alba)

Summary1.We investigated the mechanisms by which the barn owl (Tyto alba) determines the azimuth and elevation of a sound source. Our measure of localizing ability was the accuracy with which the owl oriented its head to a sound source.2.When localizing tonal signals, the owl committed the smallest errors at frequencies between 4 and 8 kHz. The azimuthal component of these errors was frequency independent from 1 to 8 kHz, but the elevational component increased dramatically for frequencies below 4 kHz.3.The owls mean error when localizing wide band noise was nearly three times less than its mean error when localizing the optimal frequency for tonal localization (6 kHz).4.Occluding the right ear caused the owl to orient below and to the left of the sound source; occluding the left ear caused it to orient above and to the right of the sound source.5.With ruff feathers (facial ruff) removed, the owl continued to localize sounds accurately in azimuth, but failed to localize sounds in elevation.6.We conclude from these results that the barn owl uses interaural comparisons of sound spectrum to determine the elevation of a sound source. Both interaural onset time and interaural spectrum are used to identify the azimuth of the sound source. If onset time is not available (as in a continuous sound), the owl can derive the azimuth of the source from interaural spectrum alone, but its spatial resolution is poorer.

Instructed learning in the auditory localization pathway of the barn owl

A bird sings and you turn to look at it — a process so automatic it seems simple. But is it? Our ability to localize the source of a sound relies on complex neural computations that translate auditory localization cues into representations of space. In barn owls, the visual system is important in teaching the auditory system how to translate cues. This example of instructed plasticity is highly quantifiable and demonstrates mechanisms and principles of learning that may be used widely throughout the central nervous system.

Sound localization by the barn owl (Tyto alba) measured with the search coil technique

Summary1.The dynamics and accuracy of sound localization by the barn owl (Tyto alba) were studied by exploiting the natural head-orienting response of the owl to novel sound stimuli. Head orientation and movement were measured using an adaptation of the search coil technique which provided continous high resolution azimuthal and elevational information during the behavior.2.The owls responded to sound sources with a quick, stereotyped head saccade; the median latency of the response was 100 ms, and its maximum angular velocity was 790°/s. The head saccade terminated at a fixation point which was used to quantify the owls sound localization accuracy.3.When the sound target was located frontally, the owls localization error was less than 2° in azimuth and elevation. This accuracy is superior to that of all terrestrial animals tested to date, including man.4.When the owls were performing open-loop localization (stimulus off before response begins), their localization errors increased as the angular distance to the target increased.5.Under closed-loop conditions (stimulus on throughout response), the owls again committed their smallest errors when localizing frontal targets, but their errors increased only out to target angles of 30°. At target angles greater than 30°, the owls localization errors were independent of target location.6.The owl possesses a frontal region wherein its auditory system has maximum angular acuity. This region is coincident with the owls visual axis.

Experience Alters the Spatial Tuning of Auditory Units in the Optic Tectum during A Sensitive Period in the Barn Owl

The auditory spatial tuning of bimodal (auditory-visual) units in the optic tectum of the barn owl was altered by raising animals with one ear occluded. Changes in spatial tuning were assessed by comparing the location of a units auditory best area with that of its visual receptive field. As shown previously, auditory best areas are aligned with visual receptive fields in the tecta of normal birds (Knudsen, E. I. (1982) J. Neurosci. 2: 1177–1194). It was demonstrated in this study that, when birds were raised with one ear occluded, best areas and visual receptive fields were aligned only as long as the earplug was in place. When the earplug was removed, best areas and visual receptive fields became misaligned, indicating that a change in auditory spatial tuning had taken place during the period of occlusion. However, in a bird that received an earplug as an adult, no such alterations in auditory spatial tuning were observed; even after 1 year of monaural occlusion, auditory best areas and visual receptive fields were misaligned so long as the earplug was in place, and were aligned when the earplug was removed. These results suggest that exposure to abnormal localization cues modifies the auditory spatial tuning of tectal units only during a restricted, sensitive period early in development. After the earplug was removed from a juvenile bird that had been raised with an occluded ear, the initial misalignment between auditory best areas and visual receptive fields decreased gradually over a period of weeks. In contrast, when earplugs were removed from two adult birds that had been raised with monaural occlusions, auditory- visual misalignments persisted for as long as measurements were made, which was up to 1 year after earplug removal. These data indicate that auditory cues become permanently associated with locations in visual space during a critical period which draws to a close at about the age when the animal reaches adulthood. Horseradish peroxidase was injected into two optic tecta (in a single animal) that contained units with permanently altered auditory spatial tuning. The positions of retrogradely labeled cells in the external nucleus of the inferior colliculus (ICX) were the same as those observed in control birds (Knudsen, E. I., and P. F. Knudsen (1983) J. Comp. Neurol. 218: 187–196). Thus, the changes in spatial tuning were not due to a shift in the topographic projection from the ICX to the optic tectum.(ABSTRACT TRUNCATED AT 400 WORDS)

Incremental training increases the plasticity of the auditory space map in adult barn owls.

The plasticity in the central nervous system that underlies learning is generally more restricted in adults than in young animals. In one well-studied example, the auditory localization pathway has been shown to be far more limited in its capacity to adjust to abnormal experience in adult than in juvenile barn owls. Plasticity in this pathway has been induced by exposing owls to prismatic spectacles that cause a large, horizontal shift of the visual field. With prisms, juveniles learn new associations between auditory cues, such as interaural time difference (ITD), and locations in visual space, and acquire new neurophysiological maps of ITD in the optic tectum, whereas adults do neither. Here we show that when the prismatic shift is experienced in small increments, maps of ITD in adults do change adaptively. Once established through incremental training, new ITD maps can be reacquired with a single large prismatic shift. Our results show that there is a substantially greater capacity for plasticity in adults than was previously recognized and highlight a principled strategy for tapping this capacity that could be applied in other areas of the adult central nervous system.

Experience-Dependent Plasticity and the Maturation of Glutamatergic Synapses

Together, these observations suggest the following general hypothesis: during early development, neural networks are established by genetically specified cues and activity-dependent processes. Glutamatergic synapses that form during this period display a rapid, activity-dependent maturation of NMDA and AMPA receptor currents, so that by the time basic networks have been established, glutamatergic pharmacology is much like that observed in the adult. Subsequently, there occurs an extended, late period of development during which established networks are modified by experience, in part through the formation and selective stabilization of novel glutamatergic synapses. These novel synapses are created initially as either synapses with long-duration NMDA receptor currents and/or as silent, purely NMDAergic synapses, recapitulating the maturation of glutamatergic synaptic currents in early development. In either case, the high NMDA/AMPA current ratio of such synapses would be beneficial in enabling rapid activity-dependent adjustment of synaptic strength by NMDA receptor-dependent mechanisms (Katz and Shatz 1996xSynaptic activity and the construction of cortical circuits. Katz, L.C and Shatz, C.J. Science. 1996; 274: 1133–1138Crossref | PubMed | Scopus (1909)See all ReferencesKatz and Shatz 1996). If novel synapses were formed as silent synapses, an additional advantage would be gained: because synapses would be made functional only if they were appropriately targeted, the presence of inappropriate synapses would not adversely affect the performance of the preexisting circuit (Cline et al. 1996xIn vivo development of neuronal structure and function. Cline, H.T, Wu, G.-Y, and Malinow, R. Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95–104Crossref | PubMedSee all ReferencesCline et al. 1996). Thus, large-scale adaptive adjustments could be made, for example, by nondirected axonal outgrowth and synapse formation, followed by the selective activation of appropriate synapses. In this model, network optimization could proceed without jeopardizing normal function, an essential feature if plasticity is to occur in a circuit that is necessary for the survival of the animal. This is certainly the case for the barn owl, in which ICX plasticity takes place at an age when juvenile owls have left the nest and depend on sound localization to find their prey. Finally, by the end of the late developmental period, which coincides with sexual maturation, the capacity for synaptogenesis is dramatically restricted, reducing the ability of many networks to adapt to novel changes in sensory or motor experience. Within the juvenile period, this restriction may occur earlier for low order networks and at progressively later ages for high order networks (Fox and Zahs 1994xCritical period control in sensory cortex. Fox, K and Zahs, K. Curr. Opin. Neurobiol. 1994; 4: 112–119Crossref | PubMed | Scopus (57)See all ReferencesFox and Zahs 1994).A prediction of this model is that, except for brain regions in which the capacity for synaptogenesis persists throughout life, experience-dependent changes in neural circuits in the adult will be mediated primarily through changes in the efficacy of the synapses that exist at the end of the juvenile period. Thus, experience during the juvenile period may be critical in establishing the repertoire of connectional states available to the adult nervous system (Knudsen 1998xCapacity for plasticity in the adult owl auditory system expanded by juvenile experience. Knudsen, E.I. Science. 1998; 279: 1531–1533Crossref | PubMed | Scopus (100)See all ReferencesKnudsen 1998).*Present address: Department of Psychiatry, Langley Porter Psychiatric Institute, Box 0984, University of California, San Francisco, California 94143.

Maps versus clusters: different representations of auditory space in the midbrain and forebrain

The auditory system determines the location of stimuli based on the evaluation of specific cues. The analysis begins in the tonotopic pathway, where these cues are processed in parallel, frequency-specific channels. This frequency-specific information is processed further in the midbrain and in the forebrain by specialized, space-processing pathways that integrate information across frequency channels, creating high-order neurons tuned to specific locations in space. Remarkably, the results of this integrative step are represented very differently in the midbrain and forebrain: in the midbrain, space is represented in maps, whereas, in the forebrain, space is represented in clusters of similarly tuned neurons. We propose that these different representations reflect the different roles that these two brain areas have in guiding behavior.

Why Seeing Is Believing: Merging Auditory and Visual Worlds

Vision may dominate our perception of space not because of any inherent physiological advantage of visual over other sensory connections in the brain, but because visual information tends to be more reliable than other sources of spatial information, and the central nervous system integrates information in a statistically optimal fashion. This review discusses recent experiments on audiovisual integration that support this hypothesis. We consider candidate neural codes that would enable optimal integration and the implications of optimal integration for perception and plasticity.

Mechanisms of experience-dependent plasticity in the auditory localization pathway of the barn owl.

Abstract Sound localization is a computational process that requires the central nervous system to measure various auditory cues and then associate particular cue values with appropriate locations in space. Behavioral experiments show that barn owls learn to associate values of cues with locations in space based on experience. The capacity for experience-driven changes in sound localization behavior is particularly great during a sensitive period that lasts until the approach of adulthood. Neurophysiological techniques have been used to determine underlying sites of plasticity in the auditory space-processing pathway. The external nucleus of the inferior colliculus (ICX), where a map of auditory space is synthesized, is a major site of plasticity. Experience during the sensitive period can cause large-scale, adaptive changes in the tuning of ICX neurons for sound localization cues. Large-scale physiological changes are accompanied by anatomical remodeling of afferent axons to the ICX. Changes in the tuning of ICX neurons for cue values involve two stages: (1) the instructed acquisition of neuronal responses to novel cue values and (2) the elimination of responses to inappropriate cue values. Newly acquired neuronal responses depend differentially on NMDA receptor currents for their expression. A model is presented that can account for this adaptive plasticity in terms of plausible cellular mechanisms.