Amygdalo-cortical sprouting continues into early adulthood: implications for the development of normal and abnormal function during adolescence

Adolescence is a critical stage for the development of emotional maturity and diverse forms of psychopathology. The posterior basolateral nucleus of the amygdala is known to mediate fear and anxiety and is important in assigning emotional valence to cognitive processes. The medial prefrontal cortex, a homologue of the human anterior cingulate cortex, mediates emotional, attentional, and motivational behaviors at the cortical level. We postulate that the development of connectivity between these two corticolimbic regions contributes to an enhanced integration of emotion and cognition during the postnatal period. In order to characterize the development of this relay, injections of the anterograde tracer biocytin were stereotaxically placed within the posterior basolateral nucleus of the amygdala of rats at successive postnatal time points (postnatal days 6-120). Labeled fibers in the medial prefrontal cortex were evaluated using a combination of brightfield, confocal, and electron microscopy. We found that the density of labeled fibers originating from the posterior basolateral nucleus shows a sharp curvilinear increase within layers II and V of the anterior cingulate cortex and the infralimbic subdivisions of medial prefrontal cortex during the late postweanling period. This increase was paralleled by a linear rise in the number of axospinous and axodendritic synapses present in the neuropil. Based on these results, we propose that late maturation of amygdalo-cortical connectivity may provide an anatomical basis for the development and integration of normal and possibly abnormal emotional behavior during adolescence and early adulthood.     

Odor discrimination in patients with frontal lobe damage and Korsakoff's syndrome

The involvement of the frontal cortex and thalamic nucleus in odor discrimination in humans was assessed. Six patients with frontal lobe brain damage, seven patients with alcoholic Korsakoff's syndrome and 16 healthy comparison subjects completed odor detection and odor discrimination tasks. Multivariate general linear modeling with age as a covariant revealed significantly decreased odor discrimination ability in frontal lobe damaged patients and marginally decreased odor discrimination ability in Korsakoff's syndrome patients as compared to the healthy comparison subjects. No deficits were found in odor detection ability. The findings suggest that in human odor discrimination, there is more involvement of cortico-cortical pathways than of thalamo-cortical pathways.     

Selective serotonin reuptake inhibitor paroxetine modulates motor behavior through practice. A double-blind,placebo-controlled,multi-dose study in healthy subjects

We hypothesized that selective serotonin reuptake inhibitors (SSRIs) could modulate motor activity in healthy subjects in a dose-dependent manner. The effects of a single dose of paroxetine were tested in a double-blind, placebo-controlled study. Six randomized and counterbalanced subjects performed behavioral tests in three sessions 1 week apart (E1, E2 and E3) at peak plasma concentration (5 h after drug intake). Each subject was given 20 mg or 60 mg of the drug, or a placebo. Tasks were the Nine Peg Hole test (three trials), Moede dexteritymeter (two trials), and compatible and incompatible reaction time tasks. The results show that at the first trials, performance did not differ after placebo or paroxetine intake. However, 20 and 60 mg of paroxetine improved performance significantly at the third trial of the Nine Peg Hole test and subjects receiving the drug performed 7% faster than those under placebo. An amount of 20 mg, but not 60 mg, of paroxetine improved dexterity significantly at the second trial of the Moede test and subjects performed 30% faster. Conversely, the drug did not affect reaction time for the compatible task and subjects were 11% slower under 20 mg with the incompatible task. Thus, paroxetine decreased the ability to inhibit automatism. Thus, it was concluded that a single dose of paroxetine improved motor performance through practice. But negative effects occurred on tasks including the inhibition of an automatism. Paroxetine enhanced brain motor output (motor activity in S1M1) [NeuroImage, 15 (2002) 26]. This S1M1 hyperactivation is likely to be responsible for the better performance. The brain effect and motor improvement were dose dependent. For both, 20 mg was the optimal dose.     

Decision-making and addiction (part II): myopia for the future or hypersensitivity to reward?

On a decision-making instrument known as the "gambling task" (GT), a subgroup of substance dependent individuals (SDI) opted for choices that yield high immediate gains in spite of higher future losses. This resembles the behavior of patients with ventromedial (VM) prefrontal cortex lesions. In this study, we addressed the possibility that hypersensitivity to reward may account for the "myopia" for the future in this subgroup of SDI. We used a variant version of the GT, in which the good decks yielded high immediate punishment but higher delayed reward. The bad decks yielded low immediate punishment and lower delayed reward. We measured the skin conductance response (SCR) of subjects after receiving reward (reward SCR) and during their pondering from which deck to choose (anticipatory SCR). A subgroup of SDI who was not impaired on the original GT performed normally on the variant GT. The subgroup of SDI who was impaired on the original GT showed two levels of performance on the variant GT. One subgroup (36% of the sample) performed poorly on the variant GT, and showed similar behavioral and physiological impairments to VM patients. The other subgroup of SDI (64% of the sample) performed normally on the variant task, but had abnormally large physiological responses to reward, i.e. large SCR after receiving reward (reward SCR) and large SCR in anticipation of outcomes that yield large reward. Thus, the combined cognitive and physiological approach of assessing decision-making characterizes three sub-populations of SDI. One sub-population is without impairments that can be detected by any measure of the GT paradigm. Another sub-population is similar to VM patients in that they are insensitive to the future, both positive and negative. A third sub-population is hypersensitive to reward, so that the presence or the prospect of receiving, reward dominates their behavior.     

Central fatigue and motor cortical excitability during repeated shortening and lengthening actions

A decline in voluntary muscle activation and adaptations in motor cortical excitability contribute to the progressive decline in voluntary force during sustained isometric contractions. However, the neuronal control of muscle activation differs between isometric and dynamic contractions. This study was designed to investigate voluntary activation, motor cortex excitability, and intracortical inhibition during fatiguing concentric and eccentric actions. Eight subjects performed 143 torque motor-controlled, repeated shortening and lengthening actions of the elbow flexor muscles. Transcranial magnetic stimulation (TMS) was applied three times every 20 cycles. Magnetic evoked motor potentials (MEP), duration of the silent period (SP), and the torque increase due to TMS were analyzed. TMS resulted in a small torque increase in unfatigued actions. With repeated actions, voluntary torque dropped rapidly and the amplitude of the TMS-induced twitches increased, especially during repeated lengthening actions. MEP area of biceps brachii and brachioradialis muscles increased during repeated actions to a similar extent during lengthening and shortening fatigue. The duration of biceps and brachioradialis SP did not change with fatigue. Thus, voluntary activation became suboptimal during fatiguing dynamic actions and motor cortex excitability increased without any changes in intracortical inhibition. The apparent dissociation of voluntary activation and motor cortex excitability suggests that the central fatigue observed, especially during lengthening actions, did not result from changes in motor cortex excitability.     

Age-related changes in the distribution of nitrotyrosine in the cerebral cortex and hippocampus of rats

A wealth of indirect evidence implicates oxidative damage of cellular constituents in aging, as well as in the pathogenesis of the neurodegenerative diseases of later years. In the present study, we have determined age-related changes in the distribution of 3-nitrotyrosine (3-NT) in the cerebral cortex and hippocampus of rats. In adult rats, no 3-NT-immunoreactive cells were found in the cerebral cortex and hippocampus, whereas 3-NT immunoreactivity was significantly increased in aged rats. Some pyramidal cells of CA3 area and granule cells of the dentate gyrus highly expressed 3-NT in aged rats. Many interneurons located within stratum pyramidale and stratum oriens of CA1 were strongly immunoreactive for 3-NT. Our first demonstrations of increased 3-NT in the cerebral cortex and hippocampus during aging implicate these areas as sites for functionally significant oxidative damage. The mechanisms underlying the increased immunoreactivity for 3-NT, and the functional implications of this increase, require elucidation.     

Tonal response patterns of primary auditory cortex neurons in alert cats

The firing rates of primary auditory cortex (A1) neurons are known to be modulated only at the onset, offset, and change of a tonal stimulus in anesthetized animals. The tonal response pattern has been rarely investigated in alert animals. We investigated the time-course of A1 neuron responses to a steady tonal stimulus in alert cats. We found four types of firing responses based on statistical evaluation of the time course of the firing rate. The tonic cells (38 cells) showed a significant (P<0.05) firing increase throughout the stimulus period after a relatively long latency (mean, 25.3 ms) with little tendency of adaptation. The phasic-tonic cells (22 cells) showed a significant firing increase throughout the stimulus period after a medium latency (19.8 ms) with tendency of adaptation to less than a half of the maximum excitation level. Phasic cells (15 cells) responded, after a short latency (10.2 ms), at onset and offset of the stimuli. The unresponsive cells (26 cells) did not show a significant firing increase during stimuli. The findings suggest that there is a functional difference between each type of cells: the tonic cells encode information of static auditory signals in their firing rates; the phasic-tonic cells, of the changing auditory signal during the stimulus period; and the phasic cells, of rapid change of the auditory signal at onset and offset.     

Region-specific alterations in insulin-like growth factor receptor type I in the cerebral cortex and hippocampus of aged rats

In the present study, we investigated age-related changes in IGF-I receptor localization in the cerebral cortex and hippocampus of Sprague-Dawley rats using immunohistochemistry. In the cerebral cortex of adult rats, weakly stained cells were seen in layers II-III and layer V/VI in several cortical regions. In aged rats, there was a significant increase in IGF-I receptor immunoreactivity in the pyramidal cells in the same cortical regions. In the hippocampus of adult rats, several moderately stained neurons were seen in CA1-3 areas and the dentate gyrus. Levels of IGF-I receptor protein increased substantially with age in the CA3 area of the hippocampus. Our first morphological data concerning the differential regulation of IGF-I receptors in aged cerebral cortex and hippocampus may provide insights into age-related changes in trophic support as well as basic knowledge required for the study of neurodegenerative diseases such as Alzheimer's disease.     

Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons

Neurons containing gamma aminobutyric acid (GABA) are widely distributed throughout the primary auditory cortex (AI). We investigated the effects of endogenous GABA by comparing response properties of 110 neurons in chinchilla AI before and after iontophoresis of bicuculline, a GABA(A) receptor antagonist, and/or CGP35348, a GABA(B) receptor antagonist. GABA(A) receptor blockade significantly increased spontaneous and driven discharge rates, dramatically decreased the thresholds of many neurons, and constricted the range of thresholds across the neural population. Some neurons with 'non-onset' temporal discharge patterns developed an onset pattern that was followed by a long pause. Interestingly, the excitatory response area typically expanded on both sides of the characteristic frequency; this expansion exceeded one octave in a third of the sample. Although GABA(B) receptor blockade had little effect alone, the combination of CGP35348 and bicuculline produced greater increases in driven rate and expansion of the frequency response area than GABA(A) receptor blockade alone, suggesting a modulatory role of local GABA(B) receptors. The results suggest that local GABA inhibition contributes significantly to intensity and frequency coding by controlling the range of intensities over which cortical neurons operate and the range of frequencies to which they respond. The inhibitory circuits that generate nonmonotonic rate-level functions are separate from those that influence other response properties of AI neurons.     

The perirhinal cortex and long-term spatial memory in rats

Two experiments examined the effects of perirhinal cortex and hippocampal neurotoxic lesions on the retention of allocentric information. Perirhinal (Expt. 1) and hippocampal rats (Expt. 2) were trained on an allocentric task until they reached a performance equal to that of the control groups. Results showed that 24 days after acquisition, during a retraining period, only the hippocampal rats presented a deficit in retention. These results suggest that the perirhinal cortex and the hippocampus can be functionally dissociated in terms of their participation in the formation of long-term spatial memory. Also, the allocentric spatial memory functions of the hippocampus seem not to depend on their afferent connections with the perirhinal cortex.