Pathways of the basal ganglia: The basal ganglia receives afferents from and provides efferents to the cerebral cortex. Efferents affecting motor activity are arranged in two pathways - direct and indirect. The direct pathway initiates movement by stimulating the motor cortex through the thalamus. On the other hand, the indirect pathway is inhibitory to movement by inhibiting the motor cortex through the thalamus. Both direct and indirect pathways are driven by excitatory glutamate from cerebral cortex neurons. When dopamine from the substantia nigra pars compacta binds to D1 receptors, it activates the direct basal ganglia pathway while when it binds to D2 receptors, it inhibits the indirect pathway, the result of both actions being promoting movement.
In the direct pathway, excitatory input from the primary and pre motor cortex stimulates substance P containing GABA neurons in the striatum (putamen mainly). These neurons will secrete inhibitory neurotransmitter GABA, which then inhibit GABA neurons in the internal segment of the globus pallidus. As these neurons are inhibited, they no longer secrete GABA hence indirectly leading to excitation of VA and VL nuclei of the thalamus. These nuclei in turn send excitatory output to the motor cortex thus initiating movement. In addition, the nigrostriatal pathway arising from the substantia nigra and ending on the striatum, secretes dopamine which binds to D1 receptors on GABA neurons in the striatum leading to excitation of the direct pathway.
In the indirect pathway, excitatory glutamate input from the cerebral cortex activates enkephalin containing GABA neurons in the striatum. They then inhibit a second set of GABA neurons in the external segment of the globus pallidus. This indirectly leads to activation of the subthalamic nucleus. Excitatory glutamate output from the subthalamic nucleus excites the GABA neurons in the internal segment of the globus pallidus. Which then inhibits VA and VL nuclei of the thalamus. This reduces activity in the motor cortex and also suppresses the direct pathway. The indirect pathway is potentiated by cholinergic neurons in the striatum. Dopamine secreting neurons of the nigrostriatal pathway bind to D2 receptors and inhibit enkephalin containing GABA neurons of the indirect pathway.
Reticular activating system or RAS: RAS is a network of neurons located in the brainstem that project to the cerebral cortex through the thalamus and hypothalamus to regulate arousal and wakefulness. The ascending fibres are part of the ascending reticular system while fibres descending from the reticular nuclei to the spinal cord form the reticulospinal tract. RAS lesions may lead to sleep disturbances like narcolepsy and hypersomnia. In PTSD or post traumatic stress disorder, RAS is hyperactive. The reticulospinal tract is involved in maintenance of tone, balance and posture. RAS is made up of three specific nuclei as follows:
Locus coeruleus nucleus with norepinephrine containing neurons. It is most active during waking and slow wave sleep.
Dorsal raphe nucleus with serotonin containing neurons. It is most active during waking and slow wave sleep.
Pedunculopontine nucleus with acetylcholine and glutamate containing neurons. This nucleus is most related to arousal states of waking and REM sleep.
Sleep physiology: Sleep consists of non-rapid eye movement or NREM and rapid eye movement or REM sleep. NREM comes first followed by REM sleep in a cyclical pattern every 90 minutes till a person awakens. The amount of sleep spent in NREM decreases and REM increases with each succeeding cycle.
NREM Sleep: With eyes open, in an awake person beta waves are seen on an EEG. Beta waves are high frequency, low voltage waves. When eyes are closed, dominant EEG waves are alpha waves, which are comparatively higher voltage. NREM sleep is induced by GABA neurons in the preoptic area of the hypothalamus and serotonin secreting raphe nuclei. NREM sleep has four stages from I to IV. In stage I, lower frequency theta waves are seen. Stage II is characterised by short bursts of high frequency called sleep spindles and large K complexes. Sleep spindles are a result of periodic interactions between thalamic and cortical neurons. Stage III and IV are characterised by slow, high voltage delta waves. Stage IV is also called deep sleep. In NREM sleep, skeletal muscles are relaxed but they maintain their tone and there is a decrease in blood pressure and heart rate.
REM Sleep: Also called paradoxical sleep as the EEG resembles that of an awake person. EEG reverts from synchronised to desynchronised. “Sawtooth” waves may be seen. It is induced by cholinergic neurons in the ascending arousal system in the brainstem. REM is characterised by rapid, sacchadic eye movements, loss of muscle tone, constriction of pupils, penile and clitoral tumescence and fluctuations in heart rate, blood pressure and respirations. NE and serotonin secreting neurons end REM sleep and help transitioning to NREM sleep.
Newborns spend 50% sleep in REM, young adults 25% while elderly spend little time in REM sleep. With aging, total sleep time is reduced, time spent in both REM and NREM is reduced, there are frequent awakenings and stage IV sleep is reduced.
CSF: Compared to blood, CSF has similar concentrations of sodium, chloride, bicarbonate ion and osmolarity, lesser concentrations of potassium, calcium, glucose, amino acids and higher levels of magnesium and creatinine. CSF pH is lower than blood. Cholesterol and proteins cannot normally enter the CSF due to bigger size although amino acids are present.
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