Adult-generated hippocampal and neocortical neurons in macaques have a transient existence.

Previously we reported that new neurons are added to the hippocampus and neocortex of adult macaque monkeys. Here we compare the production and survival of adult-generated neurons and glia in the dentate gyrus, prefrontal cortex, and inferior temporal cortex. Twelve adult macaques were injected with the thymidine analogue BrdUrd, and the phenotypes of labeled cells were examined after 2 h, 24 h, 2 wk, 5 wk, 9 wk, and 12 wk by using the following immunocytochemical markers: for immature and mature neurons, class III beta-tubulin (TuJ1); for mature neurons, neuronal nuclei; for astrocytes, glial fibrillary acidic protein; and for oligodendrocytes, 2',3'-cyclic nucleotide 3' phosphodiesterase. We found that the dentate gyrus had many more BrdUrd-labeled cells than either neocortical area. Furthermore, a greater percentage of BrdUrd-labeled cells expressed a neuronal marker in the dentate gyrus than in either neocortical area. The number of new cells in all three areas declined by 9 wk after BrdUrd labeling, suggesting that some of the new cells have a transient existence. BrdUrd-labeled cells also were found in the subventricular zone and in the white matter between the lateral ventricle and neocortex; some of the latter cells were double-labeled for BrdUrd and TuJ1. Adult neocortical neurogenesis is not restricted to primates. Five adult rats were injected with BrdUrd, and after a 3-wk survival time, there were cells double-labeled for BrdUrd and either TuJ1 or neuronal nuclei in the anterior neocortex as well as the dentate gyrus.

Direction of motion discrimination after early lesions of striate cortex (V1) of the macaque monkey.

Previous studies have established that humans and monkeys with damage to striate cortex are able to detect and localize bright targets within the resultant scotoma. Electrophysiological evidence in monkeys suggests that residual vision also might include sensitivity to direction of visual motion. We tested whether macaque monkeys with longstanding lesions of striate cortex (V1), sustained in infancy, could discriminate visual stimuli on the basis of direction of motion. Three monkeys with unilateral striate cortex lesions sustained in infancy were tested 2-5 years postlesion on a direction of motion discrimination task. Each monkey was trained to make saccadic eye movements to a field of moving dots or to withhold such eye movements, depending on the direction of motion in a coherent random dot display. With smaller motion displays, monkeys were unable to detect or discriminate motion within the scotoma, although they could discriminate moving from static stimuli. Yet, each monkey was able to discriminate direction of motion when the motion stimulus was larger, but still confined to the scotoma. The results demonstrate that the recovery after infant damage to striate cortex includes some sensitivity to direction of visual motion.

Neurogenesis in the adult brain: death of a dogma.

For over 100 years a central assumption in the field of neuroscience has been that new neurons are not added to the adult mammalian brain. This perspective examines the origins of this dogma, its perseverance in the face of contradictory evidence, and its final collapse. The acceptance of adult neurogenesis may be part of a contemporary paradigm shift in our view of the plasticity and stability of the adult brain.

Neurogenesis in the neocortex of adult primates.

In primates, prefrontal, inferior temporal, and posterior parietal cortex are important for cognitive function. It is shown that in adult macaques, new neurons are added to these three neocortical association areas, but not to a primary sensory area (striate cortex). The new neurons appeared to originate in the subventricular zone and to migrate through the white matter to the neocortex, where they extended axons. These new neurons, which are continually added in adulthood, may play a role in the functions of association neocortex.

'Psychosurgery' in renaissance art.

Hieronymus Bosch and other early Renaissance artists depicted 'stone operations' in which stones were supposedly surgically removed from the head as a treatment for mental illness. These works have usually been interpreted either as portraying a contemporary practice of medical charlatans or as an allegory of human folly, rather than a real event. As trepanation for head injury and mental disease was actually carried out in Europe at this time, another interpretation of these works is that they are derived from a common medical practice of the day.

Dynamic representation of eye position in the parieto-occipital sulcus.

Dynamic representation of eye position in the parieto-occipital sulcus. Area V6A, on the anterior bank of the parieto-occipital sulcus of the monkey brain, contains neurons sensitive both to visual stimulation and to the position and movement of the eyes. We examined the effects of eye position and eye movement on the activity of V6A neurons in monkeys trained to saccade to and fixate on target locations. Forty-eight percent of the neurons responded during these tasks. The responses were not caused by the visual stimulation of the fixation light because extinguishing the fixation light had no effect. Instead the neurons responded in relation to the position of the eye during fixation. Some neurons preferred a restricted range of eye positions, whereas others had more complex and distributed eye-position fields. None of these eye-related neurons responded before or during saccades. They all responded postsaccadically during fixation on the target location. However, the neurons did not simply encode the static position of the eyes. Instead most (88%) responded best after the eye saccaded into the eye-position field and responded significantly less well when the eye made a saccade that was entirely contained within the eye-position field. Furthermore, for many eye-position cells (45%), the response was greatest immediately after the eye reached the preferred position and was significantly reduced after 500 ms of fixation. Thus these neurons preferentially encoded the initial arrival of the eye into the eye-position field rather than the continued presence or the movement of the eye within the eye-position field. Area V6A therefore contains a representation of the position of the eye in the orbit, but this representation appears to be dynamic, emphasizing the arrival of the eye at a new position.

Hippocampal neurogenesis in adult Old World primates.

The production of new hippocampal neurons in adulthood has been well documented in rodents. Recent studies have extended these findings to other mammalian species, such as tree shrews and marmoset monkeys. However, hippocampal neurogenesis has not been demonstrated in adult Old World primates. To investigate this possibility, we injected 11 adult Old World monkeys of different ages (5-23 years) with the thymidine analog bromodeoxyuridine and examined the fate of the labeled cells at different survival times by using neuronal and glial markers. In the young-adult and middle-aged monkeys, we found a substantial number of cells that incorporated bromodeoxyuridine and exhibited morphological and biochemical characteristics of immature and mature neurons. New cells located in the dentate gyrus expressed a marker of immature granule neurons, Turned On After Division 64 kDa protein, as well as markers of mature granule neurons including neuron specific enolase, neuronal nuclei, and the calcium-binding protein calbindin. Fewer new cells expressed the astroglial marker glial fibrillary acidic protein. Evidence of neurogenesis was observed in the oldest monkeys (23 years) as well, but it appeared to be less robust. These results indicate that the adult brains of Old World monkeys produce new hippocampal neurons. Adult macaque monkeys may provide a useful primate model for studying the functional significance of adult neurogenesis.

A neuronal representation of the location of nearby sounds.

Humans can accurately perceive the location of a sound source-not only the direction, but also the distance. Sounds near the head, within ducking or reaching distance, have a special saliency. However, little is known about this perception of auditory distance. The direction to a sound source can be determined by interaural differences, and the mechanisms of direction perception have been studied intensively; but except for studies on echolocation in the bat, little is known about how neurons encode information on auditory distance. Here we describe neurons in the brain of macaque monkeys (Macaca fascicularis) that represent the auditory space surrounding the head, within roughly 30 cm. These neurons, which are located in the ventral premotor cortex, have spatial receptive fields that extend a limited distance outward from the head.

Functional differentiation along the anterior-posterior axis of the hippocampus in monkeys.

We tested whether the primate hippocampus was functionally heterogenous along its anterior-posterior axis. Two monkeys were trained on both a spatial and nonspatial memory task and the incidence of spatial and nonspatial delay activity in the anterior, middle, and posterior hippocampus was noted. Spatial delay activity (activity in the delay period after the sample stimulus on the spatial memory task) was more common in the posterior than the anterior hippocampus, whereas nonspatial delay activity (activity in the delay period after the sample stimulus on the nonspatial memory task) was evenly distributed throughout the hippocampus. Furthermore, delay neurons in the anterior hippocampus exhibited scalloping delay activity, whereas those in the middle and posterior hippocampus did not. These findings suggest that the hippocampus is functionally heterogeneous and that the posterior regions may be more important for processing spatial information, whereas the anterior regions may be more important for directing or coding movements to points in space.

Spatial maps for the control of movement.

Neurons in the ventral premotor cortex of the monkey encode the locations of visual, tactile, auditory and remembered stimuli. Some of these neurons encode the locations of stimuli with respect to the arm, and may be useful for guiding movements of the arm. Others encode the locations of stimuli with respect to the head, and may be useful for guiding movements of the head. We suggest that a general principle of sensory-motor integration is that the space surrounding the body is represented in body-part-centered coordinates. That is, there are multiple coordinate systems used to guide movement, each one attached to a different part of the body. This and other recent evidence from both monkeys and humans suggest that the formation of spatial maps in the brain and the guidance of limb and body movements do not proceed in separate stages but are closely integrated in both the parietal and frontal lobes.

Rembrandt's 'The anatomy lesson of Dr. Joan Deijman'.

Rembrandt's striking painting of a human brain being dissected by a headless figure is actually a fragment of a larger work. The original was both a commissioned group portrait of a surgeons' guild and an account of a public dissection. Such dissections served both educational and entertainment functions in 17th century Holland.

Visual responses with and without fixation: neurons in premotor cortex encode spatial locations independently of eye position.

The ventral premotor cortex (PMv) of the macaque monkey contains neurons that respond both to visual and to tactile stimuli. For almost all of these "bimodal" cells, the visual receptive field is anchored to the tactile receptive field on the head or the arms, and remains stationary when the eyes fixate different locations. This study compared the responses of bimodal PMv neurons to a visual stimulus when the monkey was required to fixate a spot of light and when no fixation was required. Even when the monkey was not fixating and the eyes were moving, the visual receptive fields remained in the same location, near the associated tactile receptive field. For many of the neurons, the response to the visual stimulus was significantly larger when the monkey was not performing the fixation task. In control tests, the presence or absence of the fixation spot itself had little or no effect on the response to the visual stimulus. These results show that even when the monkey's eye position is continuously changing, the neurons in PMv have visual receptive fields that are stable and fixed to the relevant body part. The reduction in response during fixation may reflect a shift of attention from the visual stimulus to the demands of the fixation task.

Coding the locations of objects in the dark.

The ventral premotor cortex in primates is thought to be involved in sensory-motor integration. Many of its neurons respond to visual stimuli in the space near the arms or face. In this study on the ventral premotor cortex of monkeys, an object was presented within the visual receptive fields of individual neurons, then the lights were turned off and the object was silently removed. A subset of the neurons continued to respond in the dark as if the object were still present and visible. Such cells exhibit "object permanence," encoding the presence of an object that is no longer visible. These cells may underlie the ability to reach toward or avoid objects that are no longer directly visible.

Visuospatial properties of ventral premotor cortex.

In macaque ventral premotor cortex, we recorded the activity of neurons that responded to both visual and tactile stimuli. For these bimodal cells, the visual receptive field extended from the tactile receptive field into the adjacent space. Their tactile receptive fields were organized topographically, with the arms represented medially, the face represented in the middle, and the inside of the mouth represented laterally. For many neurons, both the visual and tactile responses were directionally selective, although many neurons also responded to stationary stimuli. In the awake monkeys, for 70% of bimodal neurons with a tactile response on the arm, the visual receptive field moved when the arm was moved. In contrast, for 0% the visual receptive field moved when the eye or head moved. Thus the visual receptive fields of most "arm + visual" cells were anchored to the arm, not to the eye or head. In the anesthetized monkey, the effect of arm position was similar. For 95% of bimodal neurons with a tactile response on the face, the visual receptive field moved as the head was rotated. In contrast, for 15% the visual receptive field moved with the eye and for 0% it moved with the arm. Thus the visual receptive fields of most "face + visual" cells were anchored to the head, not to the eye or arm. To construct a visual receptive field anchored to the arm, it is necessary to integrate the position of the arm, head, and eye. For arm + visual cells, the spontaneous activity, the magnitude of the visual response, and sometimes both were modulated by the position of the arm (37%), the head (75%), and the eye (58%). In contrast, to construct a visual receptive field that is anchored to the head, it is necessary to use the position of the eye, but not of the head or the arm. For face + visual cells, the spontaneous activity and/or response magnitude was modulated by the position of the eyes (88%), but not of the head or the arm (0%). Visual receptive fields anchored to the arm can encode stimulus location in "arm-centered" coordinates, and would be useful for guiding arm movements. Visual receptive fields anchored to the head can likewise encode stimuli in "head-centered" coordinates, useful for guiding head movements. Sixty-three percent of face + visual neurons responded during voluntary movements of the head. We suggest that "body-part-centered" coordinates provide a general solution to a problem of sensory-motor integration: sensory stimuli are located in a coordinate system anchored to a particular body part.

The effects of combined superior temporal polysensory area and frontal eye field lesions on eye movements in the macaque monkey.

We previously found [42] that lesions of the superior temporal polysensory area (STP) cause temporary deficits in the production of eye movements. In order to both define regions participating in the ensuing recovery and to further explore the cortical control of eye movements, we examined the effects of addition of frontal eye field (FEF) lesions to STP lesions, on visual fixation, saccadic eye movements, and smooth pursuit eye movements. Three monkeys received bilateral STP lesions followed by a FEF lesion and as a control, an additional monkey received a bilateral inferior temporal cortex (IT) lesion followed by a FEF lesion. All animals had a profound impairment in foveating the central fixation point. This impairment was completely eliminated by turning on a dim light in the testing chamber. Large neglect-like impairments in making saccades were only seen after combined STP and FEF lesions. Impairments in making smooth pursuit eye movements after combined lesions of STP and FEF were larger than those seen after STP lesions but within the range of deficits that have been reported after FEF lesions alone. The impairment of visual fixation in darkness and the lack of impairment under conditions of dim illumination appear to reflect a specific role for the FEF in spatial orientation in the absence of visual landmarks. The FEF also appears to play a more critical role than STP in smooth pursuit. By contrast, STP and the FEF appear to work cooperatively with respect to the production of saccades. We suggest that cortical oculomotor control can flow either through the midbrain or through the FEF and that the FEF pathway is specifically involved in tasks with a discontiguity between the stimuli and the behavioral response while the midbrain pathways are preferentially involved in more stimulus-driven eye movements.

Greater residual vision in monkeys after striate cortex damage in infancy.

1. Monkeys with large unilateral surgical ablations of striate cortex, sustained either in adulthood or at 5-6 wk of age, were trained on an oculomotor detection and localization task and tested with visual stimuli in the hemifields ipsilateral and contralateral to the lesion 2-5 yr after surgery. 2. Monkeys with lesions sustained in adulthood were largely unable to detect stimuli in the hemifield contralateral to the lesion, with only one monkey showing recovery toward the end of testing. Monkeys with lesions of striate cortex made in infancy, however, each showed residual detection capacity at the beginning of testing and improved to near normal by the end of testing. 3. Each of the monkeys showing a residual ability to detect within the contralateral hemifield was also able to localize visual targets with eye movements. 4. These findings demonstrate that the vision surviving striate cortex damage in primates is more robust after early damage as has been shown to be the case for primary somatosensory, motor, and association cortex.

The effects of superior temporal cortex lesions on the processing and retention of auditory information in monkeys (Cebus apella).

Three monkeys with extensive preoperative training on visual and auditory memory tasks (delayed matching-to-sample), an auditory pattern-discrimination task, and a visual serial-order task, received bilateral lesions of the superior temporal (ST) cortex in two stages, with testing after each lesion. Unilateral ST cortex lesions resulted in only moderate auditory memory impairments, whereas bilateral ST cortex lesions resulted in severe auditory memory impairments. The bilateral ST cortex lesions also resulted in severe impairments in the ability to relearn the auditory pattern-discrimination task. In contrast to the auditory impairments, neither unilateral nor bilateral ST cortex lesions had any effect whatsoever on either visual memory or visual serial-order behavior. These findings indicate that the ST cortex plays a role in auditory processing and retention similar to that played by the inferior temporal cortex for visual processing and retention.

Localization of visual stimuli after striate cortex damage in monkeys: parallels with human blindsight.

Blindsight is a phenomenon in which human patients with damage to striate cortex deny any visual sensation in the resultant visual field defect but can nonetheless detect and localize stimuli when persuaded to guess. Although monkeys with striate lesions have also been shown to exhibit some residual vision, it is not yet clear to what extent the residual capacities in monkeys parallel the phenomenon of human blindsight. To clarify this issue, we trained two monkeys with unilateral lesions of striate cortex to make saccadic eye movements to visual targets in both hemifields under two conditions. In the condition analogous to clinical perimetry, they failed to initiate saccades to targets presented in the contralateral hemifield and thus appeared "blind." Only in the condition where the fixation point was turned off simultaneously with the onset of the target--signaling the animal to respond at the appropriate time--were monkeys able to localize targets contralateral to the striate lesion. These results indicate that the conditions under which residual vision is demonstrable are similar for monkeys with striate cortex damage and humans with blindsight.

Effects of superior temporal polysensory area lesions on eye movements in the macaque monkey.

1. On the basis of its anatomic connections and single-unit properties, the superior temporal polysensory area (STP) would seem to be primarily involved in visuospatial functions. We have examined the effects of lesions of STP on saccadic eye movements, visual fixation, and smooth pursuit eye movements to directly test the hypothesis that STP is involved in visuospatial and visuomotor behavior. 2. Seven monkeys were trained to make saccades to targets 8, 15, and 22 degrees from a central fixation point along the horizontal meridian and 8 degrees from the central fixation point along the vertical meridian. One monkey was also trained to make saccades to auditory targets. The same monkeys were trained to foveate a stationary central fixation point and to follow it with a smooth pursuit eye movement when it began moving 5, 13, or 20 degrees/s. Four monkeys received unilateral STP lesions, one received a bilateral STP lesion, and as a control, two received unilateral inferior temporal cortex (IT) lesions. After testing, three of the animals with unilateral STP lesions received an additional STP lesion in the hemisphere contralateral to the first lesion. Similarly, one animal with a unilateral IT lesion received an additional IT lesion in the hemisphere contralateral to the first lesion. 3. All monkeys with complete removal of STP showed a significant increase in saccade latency to the most peripheral contralateral target, and most also had increased saccade latencies to the other contralateral targets. Saccades directed to targets along the vertical meridian or toward targets in the hemifield ipsilateral to the lesion were not impaired by removal of STP. By contrast, IT lesions did not impair the monkeys' ability to make saccadic eye movements to visual stimuli at any location, showing that saccades to visually guided targets are not impaired nonspecifically by damage to visual cortex. 4. The deficit in making eye movements after STP lesions was specific to saccade latency, with little effect on the accuracy of saccades to visual targets. 5. In the one monkey trained to make saccades to auditory targets, removal of STP did not impair saccades to auditory targets contralateral to its lesion, despite this monkey showing the largest increase in saccades latencies to visual targets. 6. There was complete recovery of saccade latency to the baseline level of performance on the saccade task after all STP lesions.(ABSTRACT TRUNCATED AT 400 WORDS)