Lecture 2 3207 PDF

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Tuesday, January 18, 2022

Chemical Control of the Brain and Behaviour Modulatory Systems of the Brain!

Diffuse Modulatory Systems! Diffuse = spread over wide area (L. diff, away) Modulatory = to exert control (L. modulus, to measure) Diffuse modulatory systems exert control over brain function across a wide area/ region. -Often performing regulatory functions; -Modulating vast assemblies of postsynaptic neurons - Requires widespread pattern of axons.

An example can be the volume, treble and bass controls – do not change the lyrics or melody of a song, but dramatically regulate the impact of both. The brain contains several diffuse modulatory systems, each of which have certain principles in common: - Small set of neurons (several thousand); - Most neurons arise from the brainstem; - Each neuron influences many others (>100,000 post-synaptic connections); - Neurons release transmitter molecules that can diffuse to many neurons (rather than confined to a specific synaptic cleft).

Detailed functioning of these diffuse modulatory systems is still being studied.

1. Noradernergic Locus Coeruleus ! Recall: Norepinephrine (NE) is used by the ANS to control target organs in the sympathetic division. NE is also produced and used by a small set of neurons in the pons(Fr. bridge) called the locus coeruleus (LC) - L. dark blue + space/spot; - Appears blue in unstained brain tissues. Each LC contains about 12,000 neurons in adult human brain. - One on each hemisphere; Cell bodies containing NE project axons diffusely -Innervate almost the entire brain; -Cerebral cortex, thalamus, hypothalamus, 1

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olfactory bulb, cerebellum, midbrain, spinal cord. -Each neuron in the LC can make ~250,000 synaptic connections around the brain. -E.g. one neuron can innervate the cerebral cortex and cerebellar cortex using axon branches.

What is the specific function of the LC? LC is involved in the regulation of -Attention; -Arousal - Sleep-wake cycles; - Learning & memory; - Anxiety; - Pain; - Mood; - Brain metabolism.

What does involve mean? Does not directly stimulate or inhibit like “classical” central transmitters (i.e. glutamate). Seems to enhance the effects of other afferent projections to the same post-synaptic targets.

Neurons of the LC are very responsive to new, unexpected, nonpainful sensory stimuli in the environment. - Brief, phasic responses to novel sensory signals; - Activity progressively slows with loss of attention. -Least activity shown under conditions of very low stimulation. - Animals not doing much; -Lack of vigilance; - Just finished a meal, sitting around digesting.

Seem to be involved in making other neurons (e.g. cerebral cortex) more responsive by speeding up information processing

2. Serotonergic Raphe Nuclei !

Serotonin-containing neurons are almost exclusively contained within the Raphe Nuclei. Raphe (G. ridge/seam) Nuclei (clusters, plural) - Nuclei lie on either side of the brainstem's midline -> seam; -9 distinct nuclei, each with unique projections within the CNS.

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Caudal nuclei (medulla) -> spinal cord Rostral nuclei (pons, midbrain)-> diffuse projections across brain. Similar to the LC, Raphe Nuclei are most active during periods of wakefulness, arousal and active states. Activity decreases significantly during sleep. Ascending Reticular Activating System -L. Rete = net; -Netlike mixture of nuclei involved in processing afferent information during periods of sleep; -Core of brainstem involved in processes that arouse and awaken the forebrain.

Raphe neurons are intimately involved in the sleepwake cycle and regulating stages of sleep.

3.Dopaminergic Modulation ! Dopamine producing neurons are located throughout the entire CNS – retina, olfactory bulb, periventricular hypothalamus, etc. However, the diffuse modulatory systems involving dopamine are contained in two closely related groups of nuclei: 1.Substantia Nigra (L. nigra, black; substantia, substance) Projects to dorsal striatum (caudate & putamen). 2.Ventral Tegmental Area (L. ventral, bottom/beneath; tegmentum, to cover) Projects to ventral striatum and prefrontal cortex.

3A. Modulation of Movement by the DA! The basal ganglia (BG) is a collection of neurons located at the base of the forebrain. -Caudate; -Putamen; - Globus Pallidus (GPe/GPi; L. Pale Body) - Subthalamic Nucleus (STN; aka ventral thalamus); - Substantia Nigra (pars compacta) -Dopamine modulates activity of BG!

Collectively, this diverse group of nuclei coordinates the motivation for movement. -Part of a system that focuses actions;

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Tuesday, January 18, 2022 -Picks the correct ones; -Does not influence activity of Lower Motor Neurons (LMN) directly.

3A. Modulation of Movement by the BG!

Dorsal striatum = input zone of the BG. Medium Spiny Neurons provide necessary dendritic branching points to collect and integrate input from a wide variety of cortical, thalamic and brainstem structures.

- Nearly all regions of the cerebral cortex project directly to striatum, which is called the corticostriatal pathway; - Multimodal association cortices ->caudate; - 1º& 2º (somato)sensory cortices ->putamen.

This suggests the corticostriatal pathway consists of multiple parallel pathways serving different functions.

Dopamine, via the substantia nigra pars compacta, is one of the most important inputs to MSNs. DA synapses selectively modulate cortical input into the BG ->located on shafts of spines; - D1 & D2 receptors provide a degree of resolution in coordinating movements.

MSN express unique K+ channel variants which results in very little spontaneous activity. -Must simultaneously receive many excitatory inputs to overcome stabilizing influence of K+conductance; - This entire process is governed by DA input.

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3A. Nigrostratal Dopamine: BA circuit !

BG circuit in PD›! !

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3B. Mesocoticolimbic Dopamine! Neurons in the VTA modulate activity in the ventral striatum and cortex. Thought to assign value to certain behaviors. Which behaviors should be repeated? -Certain behaviors are reinforced; - Behaviors that are adaptive are typically reinforced by this system.

4. Cholinergic Basal Forebrain And Brain Stem Complexes ! Recall: ACh activity at nicotinic ACh receptors produces very rapid EPSPs; however, activity at mAChR is much more delayed and controlled. Which do you think exerts diffuse modulatory function? There are 10 – 100X more mAChR vs. nAChR in the brain. The two major diffuse modulatory cholinergic system in the brain are called the basal forebrain complex and the pontomesencephalotegmental complex.

Basal Forebrain Complex - Located at base of forebrain; - Neurons are scattered among several nuclei.

Basal Forebrain Complex includes the: - Medial Septal Nuclei - Provides cholinergic innervation to hippocampus - Basal Nucleus of Meynert - Provides cholinergic innervation to neocortex. Detailed information on the function of these cells is basically nonexistent. Seem to modulate processes involved in learning & memory. The pontomesencephalotegmental complex are ACh using neurons. -2nd cholinergic diffuse modulatory system; -Acts mainly on dorsal thalamus to regulate sensory relay nuclei (more or less excitable);

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Summary of Diffuse Modulatory Systems ! In summary, there are four primary diffuse modulatory systems in the brain -> modulate activity of extremely large populations of neurons. 1.Norepinephrine LC 2.Serotonin Raphe Nuclei 3.Dopamine SN & VTA 4. Acetylcholine Basal Forebrain Complex & Pontomesencephalotegmental Complex

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