The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications.

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.

Evidence of a breakdown of corticostriatal connections in Parkinson's disease.

Dendritic spines are important structures which receive synaptic inputs in many regions of the CNS. The goal of this study was to test the hypothesis that numbers of dendritic spines are significantly reduced on spiny neurones in basal ganglia regions in Parkinson's disease as we had shown them to be in a rat model of the disease [Exp Brain Res 93 (1993) 17]. Postmortem tissue from the caudate and putamen of patients suffering from Parkinson's disease was compared with that from people of a similar age who had no neurological damage. The morphology of Golgi-impregnated projection neurones (medium-sized spiny neurones) was examined quantitatively. The numerical density of dendritic spines on dendrites was reduced by about 27% in both nuclei. The size of the dendritic trees of these neurones was also significantly reduced in the caudate nucleus from the brains of PD cases and their complexity was changed in both the caudate nucleus and the putamen. Dendritic spines receive crucial excitatory input from the cerebral cortex. Reduction in both the density of spines and the total length of the remaining dendrites is likely to have a grave impact on the ability of these neurones to function normally and may partly explain the symptoms of the disorder.

Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway.

In the 6-hydroxydopamine model of Parkinson's disease in the rat, there is a significant reduction in the number of dendritic spines on the principal projection neurons in the neostriatum, presumably attributable to loss of the nigrostriatal dopamine input. These spines invariably receive input from terminals forming asymmetric synapses that originate mainly from the cortex. The object of the present study was to determine the fate of those terminals after the loss of dendritic spines. Unbiased estimates of synaptic density and absolute numbers of synapses in a defined volume of the neostriatum were made using the "disector" and Cavalieri techniques. Numerical synaptic density of asymmetric synaptic contacts was 17% lower in the neostriatum deprived of dopamine innervation and, in absolute terms, there were 3 billion (19%) fewer contacts. The numerical density of a subpopulation of asymmetric contacts on dendritic spines that have complex or perforated synaptic specializations and normally make up 9% of the asymmetric population was 44% higher on the experimental side. Asymmetric synapses were found to be enriched in glutamate using postembedding immunogold labeling. The present observations demonstrate that the loss of spines previously reported after 6-hydroxydopamine lesions is accompanied by a loss of asymmetric synapses rather than by the movement of synapses from spines to other postsynaptic targets. The study also demonstrates that there is an increase in complex synaptic interactions that have been implicated in synaptic plasticity in other regions of the CNS after experimental manipulations.

Plasticity of striatopallidal terminals following unilateral lesion of the dopaminergic nigrostriatal pathway: a morphological study.

In Parkinson's disease the dopaminergic nigrostriatal pathway degenerates, resulting in an imbalance in activity of two pathways of information flow through the basal ganglia. In animal models of the disease, the striatonigral pathway becomes underactive and the striatopallidal pathway becomes overactive. In the present study immunocytochemistry for enkephalin and GABA and anterograde labelling were used to investigate whether morphological plasticity occurs in striatopallidal terminals following unilateral removal of the nigrostriatal dopaminergic pathway. Pallidal terminals were immunostained to reveal enkephalin and examined in the electron microscope (n=399). Immunoreactive synaptic bouton profiles were on average 64% larger on the experimental side 26 days after the lesion. Analysis of their shape revealed that those on the dopamine-depleted side of the brain were more irregular in profile and that their synaptic specialisations were more complex in shape but not significantly different in length. Striatopallidal terminals were also identified by GABA immunocytochemistry combined with anterograde labelling (n=20). Double-labelled boutons were significantly larger in cross-sectional area on the experimental side (57%). Analysis of terminals that were simply labelled by the immunogold method to reveal GABA (n=278) showed no significant differences in size between terminals from the dopamine-depleted and control side. This suggests that a substantial number of GABAergic terminals in the globus pallidus do not belong to the striatopallidal population of terminals. These morphological changes correlate with previous studies suggesting striatopallidal boutons are more active after destruction of dopaminergic input to the neostriatum.

Elderly men and women are less responsive to startling noises: N1, P3 and blink evidence.

Previously we observed that the P3 component of the event-related brain potential (ERP) elicited by startling noises, and to a lesser extent P3 to target tones, is reduced in the elderly (Ford & Pfefferbaum, 1991). In the current experiment, we tried to eliminate possible effects of age-related hearing deficits on the responses to noises by filtering them to include only frequencies heard best by the elderly (0-1000 Hz) and by setting noise intensity relative to each subject's threshold (sensation level, SL). Twelve younger (mean 22 years) and 12 older (mean 69 years) men and women listened to three sequences of tones (80%, 500 Hz, 70 dB SPL) and noises (20%). One type of noise occurred in each sequence (wide band noise set to 107 dB SPL, narrow band noise set to 107 dB SPL, or narrow band noise set to approximately 65 dB SL). The order of the three sequences was counterbalanced across age and sex. Younger subjects blinked to the noise 4-5 times more often than older subjects and had N1 and P3 amplitudes that were 2-3 times larger, regardless of the noise type. N1 amplitude to the background frequent tones and non-startle blinks did not differ between groups. Thus, even when noises were narrow band and set relative to each subject's threshold, older subjects were less responsive to startling auditory stimuli than were younger.

Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway.

Destruction of the dopamine-containing neurons in the rat substantia nigra results in morphological changes in the striatum which have been characterized at both the light and electron microscopic levels. After a unilateral 6-hydroxydopamine injection into the medial forebrain bundle, Golgi-impregnated medium-sized spiny neurons in the neostriatum ipsilateral to the injection had a lower density of spines on their dendrites than those on the contralateral side. A similar decrease in spine density was apparent from 12 days until at least 13.5 months after the lesion. A bilateral loss of spines occurred with increasing age regardless of the presence or absence of the nigrostriatal dopaminergic pathway. At the ultrastructural level, the general pattern of synaptic input to the Golgi-impregnated medium-sized spiny neurons was similar on both sides of the brain. The most obvious class of afferent boutons contacting these spiny neurons formed prominent asymmetrical synaptic specializations with the heads of the spines. The numbers of asymmetric synaptic profiles counted in random electron micrographs from the striata ipsilateral and contralateral to the lesion were not significantly different from each other. A small but significant increase in the length of asymmetric synaptic specialization profiles was, however, detected in the striata lacking a dopamine input.

A light and electron microscopical study of enkephalin-immunoreactive structures in the rat neostriatum after removal of the nigrostriatal dopaminergic pathway.

The pattern of enkephalin immunoreactivity was examined in the adult rat neostriatum, at various times after unilateral removal of the nigrostriatal dopamine input by 6-hydroxydopamine injection into the medial forebrain bundle. Animals were examined 12 days, 26 days or 13 months after the lesion. Enkephalin-immunoreactive synaptic boutons (n = 1018) in the control and the dopamine-depleted neostriatum were analysed in the electron microscope. The area of enkephalin-immunoreactive synaptic bouton profiles was significantly larger in the dopamine-depleted neostriatum and this increase was maximal in rats in which the lesion had been made 26 days or 13 months previously (50% increase). The synaptic specializations of these enkephalin-immunoreactive boutons were significantly longer in the neostriatum from the injected side. Dendritic shafts were the principal postsynaptic target of these boutons (67%) but dendritic spines (18%), perikarya (6.5%) and unidentifiable small dendrites or spines (8.5%) were also contacted. The proportions of enkephalin-immunoreactive boutons on the different postsynaptic targets were not altered by the 6-hydroxydopamine lesion. The increase in enkephalin immunoreactivity observed in the dopamine-depleted neostriatum in previous studies may be explained by the increase in the size of enkephalin-immunoreactive synaptic boutons found in the present ultrastructural investigation. The observations do not rule out the possibility that there is also an increase in the number of immunoreactive synaptic boutons, due to, for example, sprouting of the existing enkephalin-containing fibres.

Spine density on neostriatal neurones changes with 6-hydroxydopamine lesions and with age.

Golgi-impregnated medium-size spiny neurones were studied in the rat neostriatum at various times after a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. At both short (12-26 days) and long (7-12 months) survival times, the density of spines was significantly lower (13%) on neostriatal neurones ipsilateral to the 6-hydroxydopamine injection. At longer times the density of spines was lower on neurones both ipsilateral and contralateral to the lesion when compared to neurones taken from short-term animals (23%).