Many neuronal features, such as membrane receptors, membrane potentials, membrane depolarizations, and secratory activity are shared with unicellular organisms and other metazoan cell types.
Ira B. Black has noted that many, if not all, "neurotransmitters" predate the appearance of animals (and in some cases eukaryotes); and hence, they also predate the emergence of neurons and synaptic clefts.
The antiquity and evolutionary emergence of these signalling molecules and their receptors in solitary and colonial unicellular organisms lacking nervous systems suggests that the primitive functions of the neurotransmitters originally operated at the cellular level, mediatating interactions between individiual cells and cell groups.
Many of these substances have been shown to regulate growth and metabolism of unicellular organisms living in colonial cell populations.
Within metazoans these substances acquired their specific roles as neurotransmitters when animals developed neurons characterized by localized synaptic cleft specializations on their cell membranes.
Similiar considerations should be made for endocrine cells and hormone substances as well.
It is of noteworthy interest that peptide hormones are not membrane permeable and operate at the cellular level via cell surface receptors; while steroid hormones diffuse thru the cell membrane and interact with the genetic apparatus of the cell.
It becomes clear that physiological integration occurs by both path and state dependent mechanisms.
Careful consideration of the unicellular role of these substances should shed light upon the role and function of these substances in animal nervous systems.
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Residing within the pharyngeal-hindbrain complex are many of the source nuclei of the global neurotransmitter systems within the central nervous system.
The efferent tracts of the global neurotransmitter systems are distributed broadly throughout the central nervous system and have overlapping domains of influence, playing an important role in the integration of higher-order cognitive functions with activity within the somatic and visceral divisions as communicated at the pharyngeal-hindbrain complex.
Each neurotransmitter system has a variety of receptor subtypes thereby allowing each neurotransmitter to act on a wide range of neuronal subsystems, ensembles, and ciruits simultaneously and differentially.
The neurotrasmitter systems of the pharyngeal-hindbrain complex function in the adaptive global binding of localized neuronal groups, subsystems, and regional complexes distributed throughout the somatic sensorimotor nervous system.
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The action of the global neurotransitter systems underlie the processes of learning and memory consolidation which require binding of diverse and distributed neuronal complexes.
The operation of these global neurotransmitter systems facilitate the formation of recategorical memory of hedonically salient environmental contingencies.
The archicortex of primitive vertebrates recieved convergent input from all of the major global neurotransmitter systems as well as inputs from surrounding telecephalic cell groups (paleocortex, archistriatum, and septum).
The mammalian hippocampal formation is evolutionarily derived from the archicortex of the primitive vertebrate telencephalon and recieves efferents from all the global neurotransmitter systems via the fimbria and fornix.
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The action of the global neurotransmitter systems are an essential component in the development and consolidation of habitual and/or reflexive behaviors that reside below the threshold of consciousness.
In mammals, the corticobulbar track projects to the medullary reticular formation and the global neurotranmitter systems enabling neocortical activity to modulate the activity of the pharyngeal-hinbrain complex.
Speculation on this arrangement suggest the possiblity for cortical regulation of hedonic state thereby facilitating the fine-tuning of CNS-ENS interactions and cognitive discriminations.
The Serotonin (5-HT) Global Neurotransmitter system originates in the Raphe Nuclei which are embedded within the network of RF fibers at the midline of the brain stem.
Some unicellular organisms utilize serotonin to regulate the growth and metabolism of cells living within a colonial or multicellular context.
The Raphe nuclei possess ascending and descending projections to most areas of the central nervous system.
| Rostral raphe nuclei send ascending projections to: | |
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| Caudal raphe nuclei send descending projections to the: | |
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Serotonin is believed to participate in the regulation of mood and sleep, as well as playing a role in behaviors associated with sexuality, appetite and vomiting.
Serotonin is often released from serotonergic varicosities along the axon, rather than from synaptic terminal buttons, and into the extra neuronal space.
After release into the extra neuronal space, it diffuses up to 20 µm to activate 5-HT dendritic receptors, as well as, 5-HT receptors located on the cell bodies and presynaptic terminals of adjacent neurons.
Serotonin is also released by enterochromaffin cells located in the visceral nerve-net of the GI tract where it activates both secretory and peristaltic reflexes, as well as activating vagal afferents.
Both of these release mechanisms are reminescient of the pre-metazoan mechanism of serotonin signalling between unicellular organisms.
An increased number of cells in the lateral aspects of the dorsal raphe is characteristic of humans and other primates.
Serotonin Nuclei according to Dahlstrom and Fuxe, 1964
Serotonin Nuclei
Serotonin Receptors And Their Subtypes
In the CNS, norepinephrine is released by the locus cereuleus and the lateral tegmental nucleus.
Norepinephrine is believed to play a role in arousal, attention, and focus.
Release of norepinephrine from the locus cereleus activates the sympathetic nervous system.
Norepinephrine is also released into the blood stream from the adrenal medulla where it acts as a vasopressor constricting the arteries and increasing the blood pressure and thereby increasing blood pressure.
| The Locus Cereleus sends projections to: | |
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| Lateral Tegmental Nucleus sends projections to: | |
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Norepinephrine and Epinephrine acts on alpha and beta adrenergic synaptic receptors.
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Dopaminergic neurons are three to four times more numerous in the CNS than the epinephrine-releasing neurons.
DA systems are generally characterised by several topographically organised projection systems.
The Periventricular System, which originates in area of the dorsal motor vagus, nucleus tractus solitarius, periaqueductal and periventricular gray and projects to the midbrain and diencephalon.
The Periventricular System is the archaic global dopamine neurotransmitter system common to all vertebrates.
| The Periventricular system sends projections to the: | |
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The Tuberoinfundibular System arises in the arcuate nucleus of the hypothalamus and projects to the median eminence where it regulates the release of prolactin from the anterior pituitary.
| The Arcuate Nucleus sends Tuberoinfundibular projections to the: | |
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The Mesolimbic pathways are part of the Limbic System originating in the midbrain Ventral Tegmental Area and projecting to the ventral striatal areas.
Mesolimbic pathways to the nucleus accumbens play an important role in the speed and dexterity of motor movements.
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The Mesolimbic pathways also influence motivated behaviours involving limbic system activity related to pleasurable situations.
| The Ventral Tegmental Area sends Mesolimbic projections to the: | |
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The Nigrostriatal pathways are part of the Basal Ganglia and originate in the Substantia Nigra Complex.
Dopamine in the caudate nucleus facilitates postural stances.
Degeneration of neurons in the Substantia Nigra complex and Nigrostriatal pathways is a major feature of Parkinson's disease and may be the primary contributor to the characteristic tremor associated with voluntary movement.
| The Substantia Nigra complex sends Nigrostriatal projections to the: | |
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The Mesocortical pathways, like the mesolimbic pathways, arises in the Ventral Tegmental Area but innervates the frontal cortex instead of the limbic system.
It is believed that these pathways are important for certain aspects of learning and memory in mammals.
| The Ventral Tegmental Area sends Mesocortical projections to the: | |
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There are two primary dopamine G protein-linked receptors:
Neurons with D2 autoreceptors acquire a mechanism for release-dependent negative-feedback inhibition of dopamine synthesis.
The pedunculopontine tegmental nucleus sends cholinergic projections to the basal ganglia as well as to every nucleus of the thalamus.
The pedunculopontine tegmental nucleus extends from the pons into the midbrain and is believed to be involved in the generation of sleep states.
Acetylcholine in the CNS is believed to play a role in excitation of postsynaptic neurons.
The cholinergic innervation of the striatum is mostly intrinsic, arising from cholinergic interneurons.
Acetylcholine is also a major neurotransmitter of the peripheral nervous system where it binds to acetylcholine receptors on striated muscle fibers.
Within the autonomic nervous system, acetylcholine acts on pre- and postganglionic parasympathetic neurons and on preganglionic sympathetic neurons.
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| Acetylcholine Group | Source Nuclei | Output Destination |
| Ch1 | Medial Septal Nucleus | Hippocampal Complex* and Thalamus |
| Ch2 | Vertical Nucleus of the Diagonal Band | Hippocampal Complex* and Thalamus |
| Ch3 | Horizontal Limb of the Diagonal Band Nucleus | Olfactory Bulb* and Thalamus |
| Ch4 | Nucleus Basalis of Meynert | Amygdala*, Cerebral Cortex*, Thalamus, and Striatum of the Basal Ganglia |
| Ch5 | Pedunculopontine Nucleus | Thalamus*, Basal Ganglia, and Cerebral Cortex |
| Ch6 | Laterodorsal Tegmental Nucleus | Thalamus*, Basal Ganglia, and Cerebral Cortex |
| Ch7 | Medial Habenula | Interpeduncular Nucleus* |
| Ch8 | Parabigeminal Nucleus | Superior Colliculus* and Thalamus |
| *Major target of innervation | ||
