CNSforum The Lundbeck Institute

Brain anatomy: Normal brain

The dopamine pathways in the brain

Dopamine is transmitted via three major pathways. The first extends from the substantia nigra to the caudate nucleus-putamen (neostriatum) and is concerned with sensory stimuli and movement. The second pathway projects from the ventral tegmentum to the mesolimbic forebrain and is thought to be associated with cognitive, reward and emotional behaviour. The third pathway, known as the tubero-infundibular system, is concerned with neuronal control of the hypothalmic-pituatory endocrine system.

The serotonin pathways in the brain

The principal centres for serotonergic neurones are the rostral and caudal raphe nuclei. From the rostral raphe nuclei axons ascend to the cerebral cortex, limbic regions and specifically to the basal ganglia. Serotonergic nuclei in the brain stem give rise to descending axons, some of which terminate in the medulla, while others descend the spinal cord.

The noradrenaline pathways in the brain

Many regions of the brain are supplied by the noradrenergic systems. The principal centres for noradrenergic neurones are the locus coeruleus and the caudal raphe nuclei. The ascending nerves of the locus coeruleus project to the frontal cortex, thalamus, hypothalamus and limbic system. Noradrenaline is also transmitted from the locus coeruleus to the cerebellum. Nerves projecting from the caudal raphe nuclei ascend to the amygdala and descend to the midbrain.

GABA pathways in a normal brain

GABA is the main inhibitory neurotransmitter in the central nervous system (CNS). GABAergic inhibition is seen at all levels of the CNS, including the hypothalamus, hippocampus, cerebral cortex and cerebellar cortex. As well as the large well-established GABA pathways, GABA interneurones are abundant in the brain, with 50% of the inhibitory synapses in the brain being GABA mediated.

The glutamate pathways in the ‘normal’ brain

In the normal brain the prominent glutamatergic pathways are: the cortico-cortical pathways; the pathways between the thalamus and the cortex; and the extrapyramidal pathway (the projections between the cortex and striatum). Other glutamate projections exist between the cortex, substantia nigra, subthalmic nucleus and pallidum. Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their importance in mental activity and neurotransmission is considerable.

The hypothalamic-pituitary-adrenal (HPA) axis

The hypothalamic-pituitary-adrenal (HPA) axis is a feedback loop that includes the hypothalamus, the pituitary and the adrenal glands. The main hormones that activate the HPA axis are corticotropin-releasing factor (CRF), arginine vasopressin (AVP) and adrenocorticotropin hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (eg hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters.

The relationship between the dopamine and glutamate pathways in the normal brain

Stimulatory glutamate projections from the cortex activate dopamine pathways in the substantia nigra pars compacta. Dopamine is the predominant neurotransmitter in the substantia nigra and there are both stimulatory and inhibitory dopamine projections from this structure to other parts of the brain. Dopamine is predominantly inhibitory on the striatum, which affects the transmission from the striatum to the cortex and can elevate the transmission of sensory information to the cortex. If transmission through the thalamus becomes excessive, confusion and psychosis, as seen in schizophrenia, can occur.  Excessive transmission through the thalamus may be caused by either an increase in dopaminergic or a decrease in glutamatergic activity; increased levels of dopamine and decreased levels of glutamate have been implicated in the pathogenesis of schizophrenia.