Barry L. Jacobs

Adult brain neurogenesis and psychiatry: a novel theory of depression

Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One of the factors that potently suppresses adult neurogenesis is stress, probably due to increased glucocorticoid release. Complementing this, we have recently found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. These and other data have led us to propose the following theory regarding clinical depression. Stress-induced decreases in dentate gyrus neurogenesis are an important causal factor in precipitating episodes of depression. Reciprocally, therapeutic interventions for depression that increase serotonergic neurotransmission act at least in part by augmenting dentate gyrus neurogenesis and thereby promoting recovery from depression. Thus, we hypothesize that the waning and waxing of neurogenesis in the hippocampal formation are important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression.

Raphe unit activity in freely moving cats: Correlation with level of behavioral arousal

Dorsal raphe unit activity in freely moving cats showed a slow, rhythmic discharge rate during quiet waking (X=2.82 +/- 0.17 spikes/sec), and displayed a strong positive correlation with level of behavioral arousal. Presentation of an auditory stimulus during quiet waking resulted in significant increases in unit activity of 112% and 39% during the first sec and first 10 sec after the stimulus, respectively. This effect rapidly habituated with repeated stimulus presentations. During active waking, unit activity was significantly increased by 22% as compared to quiet waking, but there was no correlation between unit activity and gross body movements. Raphe unit activity showed a significant decrease of 17% during drowsiness (first appearance of EEG synchronization) as compared to quiet waking, and then progressive decreases during the early (--34%), middle (--52%) and late (--68%) phases of slow wave sleep. During all phases of slow wave sleep, the occurrence of sleep spindles was frequently associated with a transitory decrease in unit activity. The discharge rate would typically decrease during the few seconds immediately preceding the spindle, remains at this low level during the occurrence of the spindle, and then increase immediately after the spindle. Raphe unit activity showed decreases of 81% during pre-REM (the 60 sec immediately before REM onset) and 98% during REM, as compared to quiet waking. Unit activity reappeared 3.2 sec before the end of REM, with significant increases in unit activity of 83% and 17% during the first sec and first 10 sec of unit activity, respectively, as compared to quiet waking. The results of these studies are discussed in relation to the hypothesis that serotonin may play a modulatory, rather than mediative, role in behavioral and physiological processes.

5-HT and motor control: a hypothesis

The activity of 5-HT-containing neurons in the brain is activated preferentially in association with motor output in cats. This is especially apparent during changes in muscle tone and during responses mediated by central pattern generators; such as chewing, locomotion and respiration. These and other data support the hypothesis that the primary functions of the 5-HT system in the brain are to facilitate motor output and concurrently inhibit sensory information processing. This hypothesis is applicable phylogenetically, from invertebrates to mammals.

Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats

Abstract Locomotor activity and regional forebrain levels of serotonin (5-HT) were measured following the placement of electrolytic lesions in either the dorsal or median raphe nucleus of adult male rats. In the first two experiments, control lesions were placed in the brachium conjunctivum, and in the third experiment, a sham lesion group served as control. Median lesions significantly increased locomotor actiivity as measured in tilt cages, by 250–300% on the second day post-lesion, and this elevation stabilized at approximately 100% above control levels on day 9 post-lesion. There were no statistically significant differences in the amount of locomotor activity in the dorsal, brachium or sham lesioned groups on any post-lesion day. When the amount of 5-HT depletion was measured 5 days post-lesion, it was found that the dorsal (D) and median (M) lesions produced similar reductions in cerebral cortex (D — 40%; M — 31%); hypothalamus (D — 54%; M — 58%) and striatum (D — 50%; M — 29%). However, the effects of the two lesions were markedly different in the hippocampus. The dorsal lesion produced a non-significant 10% reduction in hippocampal 5-HT level, while the median lesion caused an 82% reduction. On the basis of these data it is hypothesized that a reduction in hippocampal 5-HT may account for the increased activity in the median lesioned group.

Activity of Serotonergic Neurons in Behaving Animals

Brain serotonergic neurons display a distinctive slow and regular discharge pattern in behaving animals. This activity gradually declines across the arousal-waking sleep cycle, becoming virtually silent during rapid eye movement sleep. The activity of these neurons, in both the pontine and medullary groups, is generally unresponsive to a variety of physiological challenges or stressors. However, these neurons are activated in association with increased muscle tone/tonic motor activity, especially if the motor activity is in the repetitive or central pattern generator mode. We interpret these data within the following theoretical framework. The primary function of the brain serotonergic system is to facilitate motor output. Concurrently, the system coordinates autonomic and neuroendocrine function with the present motor demand, and inhibits information processing in various sensory pathways. Reciprocally, when the serotonin system is briefly inactivated (e.g., during orientation to salient stimuli), this disfacilitates motor function and disinhibits sensory information processing. It is within this context that serotonin exerts its well-known effects on pain, feeding, memory, mood, etc.

Single unit activity of locus coeruleus neurons in the freely moving cat: I. During naturalistic behaviors and in response to simple and complex stimuli

The single unit activity of presumed noradrenergic (NE) neurons in the area of the locus coeruleus (LC) was recorded in freely moving cats. Consistent with previous reports, the activity of LC neurons was found to be state dependent: active waking greater than quiet waking greater than slow wave sleep greater than REM sleep (virtually silent). The activity of these neurons showed no relationship to movement per se. In response to simple sensory stimulation, LC units showed a short latency, short duration excitatory response. In response to a variety of non-noxious naturalistic stimuli, e.g. rats, food and a conspecific, LC unit activity did not increase above an active waking baseline. However, in response to noxious stimuli, e.g. pinches, visual threats, emesis, and forced treadmill running, LC unit activity increased above that during active waking and reached its highest levels. These data, in conjunction with those in the following report, are consistent with a general role for NE-LC neurons in the organisms adaptive response to environmental and physiological challenges.

Serotonin and motor activity

The activity of brain serotonergic neurons in both the pontine-mesencephalic and medullary groups is positively correlated with the level of behavioral arousal and/or the behavioral state. This, in turn, appears to be related to the level of tonic motor activity, especially as manifested in antigravity muscles and other muscle groups associated with gross motor activity. In addition, a subset of serotonergic neurons displays a further increase in activity in association with repetitive, central pattern generator mediated responses. Accumulating evidence indicates that this relation to motor activity is related both to the co-activation of the sympathetic nervous system and to the modulation of afferent inputs.

Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine

Administration of p-chloroamphetamine (PCA) (2.5-10.0 mg/kg) or fenfluramine (FF) (5.0-15.0 mg/kg) to rats induces a behavioral syndrome--consisting of tremor, rigidity, Straub tail, hindlimb abduction, lateral head weaving and reciprocal forepaw treading--which is a reflection of the activity of central serotonin-mediated synapses. The syndrome appears within 3-5 min following i.p. administration of PCA or FF, and the syndrome-inducing effects of PCA and FF are blocked by prior depletion of serotonin with p-chlorophenylalanine. By contrast, the syndrome-inducing effect of 5-methoxy-N,N-dimethyltryptamine (5-M-DMT), which directly stimulates postsynaptic serotonin receptors, is not changed by prior serotonin depletion. Catecholamine depletion with alpha-methyl-p-tyrosine produces essentially no change in the syndrome-inducing effects of PCA, FF or 5-M-DMT. These data indicate that the initial effect of PCA or FF administration is the rapid functional release of stored serotonin.

Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat.

In light of evidence implicating dopamine in the pathophysiology of attention deficit disorder and schizophrenia, diseases involving attentional or sensory processing abnormalities, it was of interest to determine whether and how dopamine neurons in the ventral tegmental area respond to sensory stimuli. The single-unit responses of ventral tegmental dopamine neurons were recorded in freely-moving cats during the presentation of brief, non-conditioned auditory and visual stimuli. Both auditory and visual stimuli produced neuronal excitation, involving a greater than 5-fold increase in the probability of burst firing followed by a period of burst inhibition. The burst nature of the single-unit response suggests that sensory-induced dopamine release at target sites was disproportionally large relative to the discharge frequency. While characteristics of the dopaminergic sensory response were similar for auditory and visual stimuli, the response latency was longer for visual stimuli. The results demonstrate that dopamine neurons in the ventral tegmental area, the site of origin for mesolimbocortical dopamine neurons, are reliably activated by non-conditioned auditory and visual stimuli.

Behavioral correlates of dopaminergic unit activity in freely moving cats

Single unit activity of dopaminergic neurons in the substantia nigra was recorded in freely moving cats under a variety of conditions. These neurons displayed their highest discharge rate during active waking (3.68 +/- 0.30 spikes/s), which was 20% greater than their discharge rate during quiet waking (3.07 +/- 0.20). Although these cells fired somewhat faster during active waking, their activity displayed no correlation with phasic EMG changes, and, in general, their activity showed little relationship to overt behavioral changes. As the cat progressed from quiet waking through slow-wave sleep and REM sleep there was no significant change in either the rate or pattern of firing of dopaminergic neurons. In addition, no correlation was observed between the activity of these neurons and either sleep spindles or PGO waves. These neurons did respond, however, to the repeated presentation of a click or light flash with excitation followed by inhibition, with no evidence of habituation. One of the most impressive changes in dopaminergic unit activity was a large decrease in association with orienting responses. This was seen in over 50% of the cells in which this relationship was examined. As the behavioral orientation habituated with repeated stimulus presentation, so did the associated dopaminergic unit suppression. In conclusion, dopaminergic neurons maintain a remarkably constant rate and pattern of firing across a variety of behaviors and states. However, this stability can be dramatically altered under special circumstances, such as during and following orienting responses.