Stephen Gold

Brain-derived neurotrophic factor and neurotrophin-3 mRNAs are expressed in ventral midbrain regions containing dopaminergic neurons

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) enhance the survival of ventral mesencephalic dopaminergic neurons. In this study, cellular distributions of mRNAs for the nerve growth factor (NGF) family of neurotrophins (NGF, BDNF, and NT-3) and the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) were evaluated in the ventral mesencephalon of adult rat to determine if the neurotrophins are synthesized in regions of the responsive dopaminergic cells. Messenger RNAs were localized by in situ hybridization of (35)S-labeled cRNA probes and emulsion autoradiography. Neurotrophin-3 cRNA labeled neurons in the ventral tegmental area, medial substantia nigra pars compacta, and retrorubral field. The distributions of NT-3 mRNA-containing and TH mRNA-containing neurons corresponded very well in these areas. Hybridization of the BDNF cRNA labeled scattered cells in corresponding fields of TH mRNA-containing neurons in both the ventral tegmental area and the medial substantia nigra pars compacta but, in contrast to NT-3 cRNA, labeled fewer cells in these areas. Somata containing BDNF mRNA were also present in surrounding regions, including the interfascicular and interpeduncular nuclei, the supramammillary region, the periaqueductal grey matter, and fields dorsal to the lateral substantia nigra. Hybridization of NGF cRNA was not observed in the ventral mesencephalon. These results demonstrate that mRNAs for NT-3 and BDNF are expressed by neurons in both the substantia nigra and ventral tegmental area of adult rat and suggest that trophic support for the dopaminergic neurons in these areas may arise from local synthesis. Moreover, these results raise the possibility that perturbations in local neurotrophin synthesis might contribute to dopamine-related disorders including Parkinsons disease and schizophrenia.

Interleukin-1β increases basic fibroblast growth factor mRNA expression in adult rat brain and organotypic hippocampal cultures

In situ hybridization was used to study the effect of IL-1 beta on acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) mRNA expression in rat brain. Intraventricular injection of recombinant human IL-1 beta did not affect hybridization to aFGF mRNA but did induce significant and widespread increases in hybridization to bFGF mRNA. IL-1 beta induced increases in bFGF mRNA were bilaterally distributed and appeared to correspond with the distribution of non-neuronal cells. Thus, hybridization was increased in regions of both gray and white matter (e.g., corpus callosum), the ependymal lining of the third ventricle, and the pia matter. In hippocampus of IL-1 beta injected rats, hybridization was markedly increased in the molecular layers but not significantly increased in the neuronal cell layers. Elevations in bFGF mRNA were transient, peaking at 8 h postinjection in most areas. To determine if IL-1 beta effects were independent of activation of the hypothalamo-pituitary-adrenal axis, and to compare the cellular localization of increases in bFGF mRNA expression induced by IL-1 beta and bFGF, the regulation of bFGF expression was also studied in organotypic hippocampal slice cultures. Treatment of cultures with either IL-1 beta or bFGF stimulated the same general distribution of increases in bFGF mRNA as seen after IL-1 beta treatment in vivo with an additional effect on immature neurons within the hilar side of stratum granulosum; hybridization of bFGF mRNA was not increased in association with the more mature neurons of stratum pyramidale or stratum granulosum. Colocalization of bFGF cRNA hybridization with immunostaining for glial fibrillary acidic protein demonstrated that increases in bFGF mRNA induced both by IL-1 beta in vivo and in vitro and by bFGF in vitro were largely associated with astroglial cells. These findings suggest that IL-1 beta induction of bFGF contributes to the coactivation of these substances following various forms of insult to the CNS and initiates a cascade of trophic interactions that regulates processes of glial proliferation, neurotrophic factor expression, and neuroprotection.

Relative concentrations and seizure‐induced changes in mRNAs encoding three AMPA receptor subunits in hippocampus and cortex

In situ hybridization was used to determine 1) the relative concentrations of mRNAs encoding different subunits of the α‐amino 3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate receptor family in select regions of rat forebrain and 2) whether limbic seizures alter the balances of the subunit mRNAs. GluR1 and GluR2 mRNA levels were about equal and were much greater than GluR3 mRNA levels in the principal neurons of each hippocampal subdivision. Probable interneurons in hippocampal molecular layers had much higher levels of GluR1 mRNA than of either GluR2 or GluR3 mRNA. Pyramidal cell layers in neo‐ and paleocortex had a balance of mRNAs that was significantly different from the balance in hippocampus: GluR1 mRNA and GluR3 mRNA levels were about equal and were substantially lower than those of GluR2 mRNA. Lesion‐induced limbic seizures caused transient changes in mRNA levels that were differentiated with regard to subunit and brain region. All three mRNAs were decreased in the pyramidal layers of cortex, and changes in hippocampal pyramidal cells were smaller. Seizure‐induced changes in granule cells of the dentate gyrus differed from all other regions examined: GluR1 mRNA was reduced to a greater degree than GluR2 mRNA, whereas GluR3 mRNA content was markedly increased. These data strongly suggest that the subunit composition of α‐amino 3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate receptors differs significantly between areas of the cortical telencephalon. Furthermore, the data indicate that aberrant patterns of physiological activity differentially influence the expression of subunit mRNAs in a region‐specific and/or cell‐type‐specific manner.

Stoichiometries of AMPA receptor subunit mRNAs in rat brain fall into discrete categories

In situ hybridization was used to estimate the relative concentrations of mRNAs encoding different subunits (GluR1‐4) of α‐amino 3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA)‐type glutamate receptors in rat brain and to test the hypothesis that within‐region expression profiles reflect a limited number of recurring patterns. Fractional subunit mRNA concentrations were calculated for 33 brain regions, and cluster analysis methods were applied to test for statistically meaningful groupings in the data. Four relatively homogeneous classes were identified and designated as AMPA receptor (AR) categories, numbered according to dominant subunit mRNAs. The AR‐1 class (47% GluR1 mRNA) was expressed by structures near the mesodiencephalic border, including basal ganglia‐related areas. The AR‐2 class (57% GluR2 mRNA) was expressed in cortex and tectum. The AR‐1,2 class (31% GluR1, 45% GluR2) was found in the largest number of regions, including such dissimilar cell fields as hippocampus and substantia nigra pars compacta. The AR‐2,3 grouping (33% GluR2, 31% GluR3) was associated with the sensory relay and reticular thalamic nuclei. It is suggested that AR‐1,2 and AR‐2, the most closely related categories in clustering space, are largely telencephalic receptors with the former predominant in the subcortex and the latter in the cortex. The AR‐2,3 class is associated with ascending sensory stations, whereas AR‐1 appears to include several smaller categories expressed by specialized systems. If the balance of subunit mRNAs is reflected at the protein level, then the present data suggest that forebrain AMPA‐type glutamate receptors can be classified into a limited number of recurring types. J. Comp. Neurol. 385:491–502, 1997.

Toward a new theory of dreaming

A new Process Scoring System for dreams was developed and applied in an intensive single-S case study that spanned 5 1/2 years and 754 dreams. In it two hypotheses derived from a new transformative theory of dreams were tested. Both the transformation hypothesis, which holds that it is possible to shift from a symbolic to a directly expressive mode of dreaming, as well as the parallelism hypothesis, which holds that the expression of affect in dreams parallels the expression of affect in waking, were supported by the results. In contrast to Freuds analytic theory, which deals with content and interprets dreams as coded symbolic messages, our transformative theory focuses on dynamic dream processes and views dreams as pictures of feelings.

A reapplication of the process scoring system for dreams

The first application of the new Process Scoring System for dreams was made in an intensive longitudinal case study of 1 S over a 5 1/2 year period. In this second application, the dreams of a sample of 5 experienced Feeling Therapy patients were compared to those of 5 control Ss. As in the first study, considerable support was found for both the transformation hypothesis, which holds that it is possible to shift from a symbolic mode of dream behavior to a directly expressive one, and the parallelism hypothesis, which holds that the expression of affect in dreams parallels the expression of affect in waking and vice versa.

Maintenance of Psychophysiological Changes in Feeling Therapy

This was the third in a series of studies on the psychophysiological effects of psychotherapy. Two earlier studies have suggested a more relaxed physiological state as measured by body temperature, pulse, and blood pressure taken immediately following therapy sessions. This study investigated the maintenance of these changes over a 10-day period among a group of 5 experienced and 5 inexperienced patients in Feeling Therapy. While neither group was able to sustain the large drops in physiological parameters which followed therapeutic sessions, the experienced patients evidenced a considerably lower level on every parameter throughout the study, suggesting possible long-term effects of this type of therapy.

PSYCHOPHYSIOLOGICAL CHANGES IN FEELING THERAPY

In an attempt to identify the physiological effects of an intense psychotherapy, for 19 new patients entering Feeling Therapy pulse, rectal temperature, and blood pressure were recorded immediately before and after 13 individual therapy sessions. 18 college students acted as controls and were similarly measured before and after 13 mock therapy sessions in which therapeutic activities were simulated. The therapy group showed significant reductions in all parameters following sessions. No significant physiological change was found in the control groups measures. The results indicate that the therapeutic process of Feeling Therapy, matched expression of feeling, may effect at least a temporary reduction in physiological tension. Previously, abreactive releases have been shown to have a similar effect.

Preliminary Study of Psychological Changes in Feeling Therapy

10 early, 10 middle, and 10 late participants in an intense, community-oriented psychotherapy (feeling therapy) were measured for differences on two standardized psychological tests (Personal Orientation Inventory and Eysenck Personality Inventory) and on responses to individual and group post-session report questionnaires. Two earlier studies had found measurable physiological changes associated with this form of therapeutic intervention and it was hypothesized that associated psychological changes might be observed. Results partially bore out this prediction; the three groups evidenced some significant differences on the Personal Orientation Inventory and Post-session Report Forms. Eysenck Personality Inventory data did not distinguish between the groups.