Phasic dopamine release in the medial prefrontal cortex enhances stimulus discrimination.

Phasic dopamine (DA) release is believed to guide associative learning. Most studies have focused on projections from the ventral tegmental area (VTA) to the striatum, and the action of DA in other VTA target regions remains unclear. Using optogenetic activation of VTA projections, we examined DA function in the medial prefrontal cortex (mPFC). We found that mice perceived optogenetically induced DA release in mPFC as neither rewarding nor aversive, and did not change their previously learned behavior in response to DA transients. However, repetitive temporal pairing of an auditory conditioned stimulus (CS) with mPFC DA release resulted in faster learning of a subsequent task involving discrimination of the same CS against unpaired stimuli. Similar results were obtained using both appetitive and aversive unconditioned stimuli, supporting the notion that DA transients in mPFC do not represent valence. Using extracellular recordings, we found that CS-DA pairings increased firing of mPFC neurons in response to CSs, and administration of D1 or D2 DA-receptor antagonists in mPFC during learning impaired stimulus discrimination. We conclude that DA transients tune mPFC neurons for the recognition of behaviorally relevant events during learning.

Bidirectional Regulation of Innate and Learned Behaviors That Rely on Frequency Discrimination by Cortical Inhibitory Neurons.

The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination.

Functional dissociation of adult-born neurons along the dorsoventral axis of the dentate gyrus.

Adult-born granule cells in the mammalian dentate gyrus have long been implicated in hippocampal dependent spatial learning and behavioral effects of chronic antidepressant treatment. Although recent anatomical and functional evidence indicates a dissociation of the dorsal and ventral regions of the hippocampus, it is not known if adult neurogenesis within each region specifically contributes to distinct functions or whether adult-born cells along the entire dorsoventral axis are required for these behaviors. We examined the role of distinct subpopulations of adult-born hippocampal granule cells in learning- and anxiety-related behaviors using low-dose focal x-irradiation directed specifically to the dorsal or ventral dentate gyrus. Our findings indicate a functional dissociation between adult-born neurons along the longitudinal axis of the dentate gyrus wherein new neurons in the dorsal dentate gyrus are required for timely acquisition of contextual discrimination while immature neurons in the ventral dentate gyrus are necessary for anxiolytic/antidepressant-related effects of fluoxetine. Interestingly, when contexts are presented with altered temporal cues, or fluoxetine is administered alongside chronic glucocorticoid treatment, this dissociation is abrogated such that adult-born neurons across the entire dorsoventral extent of the dentate gyrus appear to contribute to these behaviors. Our results suggest that individual subpopulations of adult-born hippocampal neurons may be sufficient to mediate distinct behaviors in certain conditions, but are required to act in concert in more challenging situations.

The primate amygdala and reinforcement: a dissociation between rule-based and associatively-mediated memory revealed in neuronal activity.

To investigate the role of the primate amygdala in stimulus-reinforcement association learning, the activity of single amygdala neurons was recorded in macaques during two memory tasks. In a visual discrimination task, a population of neurons (17/659) was analyzed which responded differentially to a visual stimulus which always indicated that the primary reinforcer fruit juice could be obtain if the monkey licked, and a different visual stimulus that indicated that the primary reinforcer aversive saline would be obtained if the monkey licked. Most (16/17) of these neurons responded more to the reward-related than the aversive visual stimulus. In a recognition memory task, the majority (12/14 analyzed) of these neurons responded equally well to the trial unique stimuli when they were shown as novel and the monkey had to not lick in order to avoid saline, and when they were shown a second time as familiar and the monkey used the rule that if he licked, fruit juice would be obtained. The responses of these amygdala neurons thus reflect the direct associations of stimuli with reinforcement, but do not reflect the reward value of the stimuli when this must be assessed based on a rule (in the recognition memory task, that a stimulus will be punished the first time it is shown, and rewarded the second). This finding also shows that these amygdala neurons respond to relatively novel stimuli in the same way as they do to stimuli that have become rewarding by stimulus-reinforcement association learning. This provides a neural basis for relatively novel stimuli to be treated as rewarding, and approached.

Characteristics of sound discrimination enhancement after sound exposure in adult rats.

The auditory perceptual capacity of adult rats was assessed with regard to performance during 2-sound-discriminative operant conditioning. If the animals were passively exposed to a sound stimulus before the conditioning, performance was improved (sound-exposure-enhanced discrimination [SED]). SED had a stimulus specificity that could not be predicted in terms of the cochleotopy. SED was obstructed by D-2-amino-5-phosphonovaleric acid, an antagonist of N-methyl-D-aspartate receptors, infused into the auditory cortex (AC). No evidence supported the hypothesis that SED was due to a change of attention or motivation or to interference in the association process (e.g., latent inhibition). These findings suggest that passive auditory experience can enhance the perceptual capacity of an adult rat's AC.

Effects of long-term continuous exposure to light on memory and anxiety in mice.

The studies on the relationship between the light/dark cycle and memory function mostly used protocols of acute disruption of the circadian rhythm. The aim of the present study is to verify the effects of long-term continuous exposure to light on memory, anxiety and motor parameters of mice tested in the plus-maze discriminative avoidance task. Mice were conditioned to choose between the two enclosed arms (one aversive and one non-aversive) while avoiding the open arms of a modified elevated plus-maze apparatus. Memory was evaluated by the time spent in the aversive enclosed arm, anxiety was evaluated by the time spent in the open arms and locomotor behavior was evaluated by number of entries in the arms of the maze. The results showed that long-term (35-42 days) continuous light exposure did not modify memory or anxiety parameters but increased locomotor activity. While the increase in locomotor behavior is in line with previous studies, the unexpected absence of alterations in memory and anxiety (reported to be influenced by the circadian rhythm) is discussed.

Cortical plasticity in perceptual learning demonstrated by transcranial magnetic stimulation.

Performance on a wide range of perceptual tasks improves with practice. Most accounts of perceptual learning are concerned with changes in neuronal sensitivity or changes in the way a stimulus is represented. Another possibility is that different areas of the brain are involved in performing a task while learning it and after learning it. Here we demonstrate that the right parietal cortex is involved in novel but not learned visual conjunction search. We observed that single pulse transcranial magnetic stimulation (TMS) to the right parietal cortex impairs visual conjunction search when the stimuli are novel and require a serial search strategy, but not once the particular search task has been learned. The effect of TMS returns when a different, novel, serial search task is presented.

Spontaneous perseverative turning in rats with radiation-induced hippocampal damage.

This study found a new behavioral correlate of lesions specific to the dentate granule cell layer of the hippocampus: spontaneous perseverative turning. Irradiation of a portion of the neonatal rat cerebral hemispheres produced hypoplasia of the granule cell layer of the hippocampal dentate gyrus while sparing the rest of the brain. Radiation-induced damage to the hippocampal formation caused rats placed in bowls to spontaneously turn in long, slow bouts without reversals. Irradiated subjects also exhibited other behaviors characteristic of hippocampal damage (e.g., perseveration in spontaneous exploration of the arms of a T-maze, retarded acquisition of a passive avoidance task, and increased horizontal locomotion). These data extend previously reported behavioral correlates of fascia dentata lesions and suggest the usefulness of a bout analysis of spontaneous bowl turning as a measure of nondiscrete-trial spontaneous alternation and a sensitive additional indicator of radiation-induced hippocampal damage.

Memory-based learning in preweanling and adult rats after infantile x-irradiation-induced hippocampal granule cell hypoplasia.

Infantile exposure to x-irradiation induced severe hippocampal granule cell hypoplasia in preweanling and young adult rats. Hippocampally damaged pups, tested at 16 days of age, showed deficits in a memory-based discrimination based on single alternations of reward and nonreward when training was conducted at a 60-s intertrial interval (ITI) but not when conducted at a 30-s ITI. This deficit was still present at the 60-s ITI in animals x-irradiated in infancy and tested at 60-65 days of age. These data provide further support for the role of the hippocampus in intermediate-term memory and demonstrate, in a developmental context, the importance of an intact hippocampus in learning that depends on nonspatial memory.

Infrared imaging in vipers: differential responses of crotaline and viperine snakes to paired thermal targets.

Pit vipers use infrared-sensitive pit organs to accurately target homeothermic prey even in the absence of visual cues. It has been suggested that other vipers, including large ambush predators of the genus Bitis, also may use radiant infrared information for predatory targeting. We compared behavioral responses of pit vipers and snakes of the viperine genus Bitis to paired targets of different temperatures (i.e. cool and warm balloons), some scented with rodent odors. The rates of tongue flicking, head turning and approaches by pit vipers (Agkistrodon contortrix and Crotalus atrox) were significantly higher toward warm targets than toward cool ones. Moreover, they all were significantly higher in pit vipers than in the vipers Bitis arietans, Bitis gabonica, and Bitis nasicornis. Bitis sp. exhibited no significant differences in their behaviors toward warm versus cool targets. Pit vipers often struck at targets (always the warm target even when paired with a prey-scented cool target), but Bitis sp. never struck at either warm or cool targets. These results show that the behavioral correlates of infrared-based predatory and/or defensive targeting differ significantly between these two groups of viperid snakes, and suggest that the neural substrates of infrared imaging in crotaline snakes are either absent or functionally distinct in viperine snakes of the genus Bitis.

Conditional discrimination learning and negative patterning in rats with neonatal hippocampal lesion induced by ionizing radiation.

This study was undertaken to investigate the associative process underlying serial feature positive conditional discrimination learning (X-->A+/A-) and the role of the hippocampus in the solution of tasks demanding a configural association strategy such as the negative patterning discrimination (XA-/X+/A+). It has been suggested that the hippocampus is essential for the learning of complex tasks, so, it is expected that hippocampal lesions would prove equally detrimental to performance in both tasks, but would not interfere with simple discrimination learning. Hippocampal lesions were made with X-radiation exposure to neonate rats after completion of a parametric study 'J. Neurosci. Methods 75 (1997) 41' that established the best radiation parameters to selectively lesion the hippocampal dentate gyrus. When adults, rats were submitted to a serial feature positive conditional discrimination task with the trials 'House light/Tone: water (H-->T+)', 'Tone: no water (T-)', and two simple discrimination with the trials 'Clicker: water (C+)' and 'Noise: no water (N-)' in Experiment I. In Experiment II, adult rats, irradiated and control, were submitted to the negative patterning task with the trials 'House light/Tone: no water (HT-)', 'House light: water (H+)', 'Tone: water (T+)', and to the non-conditional discrimination with the trial Noise: no water (N-)'. In contrast to the expectation of impaired performance in these tasks by lesioned rats, animals with damage to the hippocampal dentate gyrus learned the complex and the simple tasks as well as control subjects. These results suggest that the dentate gyrus does not participate directly in the modulation of acquisition of tasks demanding a complex strategy of occasion setting in procedures of serial conditional discrimination or a configural strategy, important for the negative patterning discrimination solution.

Cranial irradiation of young rats impairs later learning and growth.

Young rats (26 days) were exposed to ionizing radiation of the head of 0, 1200, 2400, or 3000 rads total in 200 rads/day doses. The subsequent growth of irradiated rats was permanently impaired: such impairment was positively related to amount of irradiation. Beginning in adolescence, rats were trained on a horizontal/vertical visual discrimination in a runway task, and although all four groups mastered the discrimination, they differed in their patterns of acquisition. These results indicate long term effects are associated with a cranial irradiation regimen similar to that given to children suffering acute lymphocytic leukemia (ALL).

Magnetic field effects on spatial discrimination and melatonin levels in mice.

Previous research has demonstrated a decrement in spatial discrimination learning following exposure to a .30 Tesla magnetic field. It had been suggested that those findings might be the result of an interaction between the magnetic field and physiological ferromagnetic material (magnetite). In the present study, mice were exposed for 100 min to a 2.0 Tesla field and both their left-right discrimination learning ability and serum melatonin levels were compared with a control group. Results indicated a significant interference with spatial discrimination learning following exposure, but no significant differences in serum melatonin levels. These findings appeared to rule out magnetically induced melatonin fatigue as an explanation of the decrement in spatial learning, as opposed to other possibilities such as magnetic effects on brain magnetite. However, additional controls are suggested for future research.

Recovery of absolute threshold with UVA-induced retinal damage.

A within-trial psychophysical procedure tracked the initial loss and subsequent recovery of visual thresholds in albino rats exposed to ultraviolet light at 350 nanometers and 0.4 milliwatts per square centimeter. Absolute thresholds increased up to 5 log units immediately following the 15 hour ultraviolet exposure, with a daily recovery of 1-2 log to asymptotic thresholds over a 7-day post-exposure period. The corresponding retinal damage on Day 1 included extensive vesiculation of the photoreceptor outer segments, vacuolation of the inner segments, and pyknosis of cell nuclei. The total number of photoreceptor nuclei and outer segments was unchanged relative to control eyes through post-exposure Day 3. Both nuclei and outer segment counts then consistently decreased 15-20 percent between Days 3-7. The two-stage loss of photoreceptors but daily recovery of absolute thresholds again suggests a significant dissociation of retinal structure and psychophysical function in light-induced ocular pathology.

Individual differences in attentional deficits and dopaminergic protein levels following exposure to proton radiation.

To assess the possible neurobehavioral performance risks to astronauts from living in a space radiation environment during long-duration exploration missions, the effects of head-only proton irradiation (150 MeV/n) at low levels (25-50 cGy, approximating an astronaut's exposure during a 2-year planetary mission) were examined in adult male Long-Evans rats performing an analog of the human psychomotor vigilance test (PVT). The rodent version of PVT or rPVT tracks performance variables analogous to the human PVT, including selective attention/inattention, inhibitory control ("impulsivity") and psychomotor speed. Exposure to head-only proton radiation (25, 50, 100 or 200 cGy) disrupted rPVT performance (i.e., decreased accuracy, increased premature responding, elevated lapses in attention and slowed reaction times) over the 250 day testing period. However, the performance decrements only occurred in a subgroup of animals at each exposure level, that is, the severity of the rPVT performance deficit was unrelated to proton exposure level. Analysis of brain tissue from irradiated and control rats indicated that only rats with rPVT performance deficits displayed changes in the levels of the dopamine transporter and, to a lesser extent, the D2 receptor. Additional animals trained to perform a line discrimination task measuring basic and reversal learning showed no behavioral effects over the same exposure levels, suggesting a specificity of the proton exposure effects to attentional deficits and supporting the rPVT as a sensitive neurobehavioral assay.

Effect of stimulus intensity on the sizes of chromatic perceptive fields.

The effects of intensity on chromatic perceptive field size were investigated along the horizontal meridian at 10 degrees temporal eccentricity by manipulating stimulus intensity from 0.3 to 3.3 log trolands. Following light adaptation, observers described the hue and saturation of monochromatic stimuli (440-660 nm, in 10 nm steps) for a series of test sizes (0.098-3 degrees) presented along the time period associated with the cone plateau of the dark-adaptation function. Perceptive field sizes of the four elemental hues (red, green, yellow, and blue) and the saturation component were estimated by three observers at each intensity level for each wavelength. In general, perceptive field sizes of blue and red are the smallest, and yellow and green are the largest. Furthermore, perceptive field sizes of all four hues decrease with increasing stimulus intensity, though the absolute change is largest for green and yellow. The decrease in size with increase in intensity cannot be completely explained in terms of saturation or rod signals and is likely, then, attributable to a cone-based mechanism.

Early postnatal x-irradiation of the hippocampus and discrimination learning in adult rats.

Rats with X-irradiation-produced degranulation of the hippocampal dentate gyrus were trained in the acquisition and reversal of simultaneous visual and tactile discriminations in a T-maze. These experiments employed the same treatment, apparatus, and procedure but varied in task difficulty. In the brightness and roughness discriminations, the irradiated rats were not handicapped in acquiring or reversing discriminations of low or low-moderate task difficulty. However, these rats were handicapped in acquiring and reversing discriminations of moderate and high task difficulty. In a Black/White discrimination, in which the stimuli were restricted to the goal-arm walls, the irradiated rats were handicapped in the acquisition (low task difficulty) and reversal (moderate task difficulty) phases of the task. These results suggest that the irradiated rats were not handicapped when the noticeability of the stimuli was high, irrespective of modality used, but were handicapped when the noticeability of the stimuli was low. In addition, these results are consistent with the hypothesis that rats with hippocampal damage are inattentive due to hyperactivity.