Enhancer regulation

Henderson A, Holloway A, Reeves R, Tremethick DJ (2004) Recruitment of SWl/SNF to the human immunodeficiency virus type 1 promoter. Mol Cell Biol 24 389-397 Hines R, Sorensen BR, Shea MA, Maury W (2004) PU.l binding to ets motifs within the equine infectious anemia virus long terminal repeat (LTR) enhancer regulation of LTR activity and virus replication in macrophages. J Virol 78 3407-3418... 

Previous sections have discussed a number of inducible promoters and their applications in nucleic acid-based therapeutics. Enhanced regulated gene expression can be achieved by combining several strategies. 

In my case the decisive period of experimentation that built into my brain the urge to clarify the unknown neurochemical mechanism of the acquisition of a drive fell between 1951 and 1953. After 50 years of continuous analysis of this problem, it has become my firm belief that the mammalian brain reached its highest level of organization with the evolution of specific cortical enhancer regulation enabling it to acquire drives. I also propose that this development culminated in the appearance of the Homo sapiens, the only mammalian species whose fife is primarily based on the acquisition of unnatural drives. It seems to me that just as the discovery of the force of mutual attraction among all bodies led to a sound interpretation of the world around us, the discovery of the force of mutual attraction between cortical neurons will lead to a sound interpretation of a brain function which is inseparable from conscious perception. 

We described earlier the essence of both the innate and acquired drives as a state of specific activation (active focus) in a special population of subcortical and cortical neurons, respectively (see Fig. 11 in Knoll 1969). In the light of the enhancer regulation concept, we may characterize the active focus as an endogenous enhancer substance-induced enhanced excitability in a circumscribed population of mesencephalic and telencephalic neurons that persists until the goal has been reached. 

In the case of innate drives enhancer regulation in the mesencephalon is responsible for both the formation of the subcortical active focus that maintains the enhanced orienting-searching reflex activity until the goal is reached and cortical active focus ( the cortical representation of the drive ). As natural conditions are always changing, even the goals determined by innate drives can be reached only with the participation of cortical neurons. The successful operation of an innate drive requires, namely, the continuous acquisition of proper chains of ECRs. 

Sexual hormones seem to be responsible for the transition from the developmental, uphill phase of life into the postdevelopmental, downhill period, characterized by the slow age-related decay of brain performance terminated by natural death (Fig. 6 in Knoll 2001). Weighty arguments speak in favor of the assumption that the slow, continuous age-related decline of enhancer regulation in the mesencephalic neurons plays a key role in the progressive decay of behavioral performances with the passing of time (see Sect. 3.5.1.1 for details). 

Enhancer Regulation A Neurochemical Approach to the Innate and Acquired Drives... 

Mesencephalic Enhancer Regulation Natural and Synthetic Mesencephalic Enhancer Substances... 

We can define enhancer regulation as the existence of enhancer-sensitive neurons capable of changing their excitability in a split second and working on a higher activity level, due to natural enhancer substances. Of the agents with such effect, for the time being, only 3-phenylethylamine (PEA) and tryptamine have been experimentally analyzed (Knoll 2001,2003). 

Though enhancer sensitive neurons exist also outside the mesencephalon, we used the term mesencephalic enhancer regulation to emphasize the key importance of the dopaminergetic neurons, the most rapidly aging neurons of the brain, primarily responsible for the progressive age related decline of behavioral performances. 

The catecholaminergic and serotonergic neurons in the mesencephalon are excellent models to study the enhancer regulation since their physiological function is to supply the brain continuously with the proper amounts of monoamines that influence - activate or inhibit - billions of neurons. The significant enhancement of the nerve-stimulation-induced release of [3H]-norepinephrine, [3H]-dopamine, and [3H]-serotonin from the isolated brain stem of the rat in the presence of PEA (Fig. 3.1) or tryptamine (Fig. 3.2) is shown to illustrate the response of enhancer-sensitive neurons to endogenous enhancer substances. 

Enhancer regulation in the brain heralds a new line of research. It brings a different perspective to brain-organized, goal-oriented behavior since it seems to represent the device in the mammalian brain that operates as the... 

The Role of (-)-Deprenyl in the Recognition of the Enhancer Regulation in the Mesencephalic Neurons... 

Further studies clarified the operation of mesencephalic enhancer regulation (Knoll and Miklya 1995 Knoll et al. 1996a,b,c). We realized that PEA, the parent compound of (-)-deprenyl, is primarily an endogenous mesencephalic enhancer substance. Since PEA, in higher concentrations, is a highly effective releaser of catecholamines from their intraneuronal stores, this effect covered up completely the enhancer effect of this endogenous amine, which was classified as the prototype of the indirectly acting sympathomimetics. 

---