01/04/16 Flashcards
Division of the Nervous System
- Peripheral and Central
Peripheral Nervous System
- Made of the somatic and the autonomic systems
- Somatic:
- “Of the body”-pertaining to the walls of the body as distinguished from the inner organs
- Receptors are distributed throught the body
- AKA: Skin senses or body senses
- 4 distinct somatic modulaties
- Touch, pain, thermal and proprioceptive
- Motor neurons: origniate in spinal cord and innervate skeletal muscle
- Autonomic:
- Ganglia that revieve info from CNS and innervate organs
- Parasympathetic and sympathetic
CNS: components and spinal cord
- Spinal cord, brain stem, and brain
- Spinal cord
- carries info to and from periphery and plays a major role in autonomic physiology
- part of CNS functioning at the lowest level
- contains both sensory and motor neurons
- danamage cause loss of sensation/paralysis
CNS: Brainstem
- Made of upper spinal cord, pons, and medulla
- Controls vegetative responses
- Medulla controls respiration and blood pressure
- Pons relays information between cerebral cortex and cerebellum
Cerebellum
- Controls motor coordination, control of movement, and motor learning
- Increasing evidence that it plays a role in motor memory
Midbrain
- Midlevel processing of visual and auditory information
Diencephalon
- Thalamus
- Integrates information between subcortical and corticol structures, a relay organ
- Hypothalamus
- Regulates body temperature, feeding, reproductive behaviors and circadian rhythm. Also mediates some pheromone responses in humans
Limbic System
- Hippocampal formation
- spatial, contextual, object recognition memory and emotion
- Amygdala
- Fear responses, emotion, and some control of the autonomic system
- Limbic lobe
- Memory and emotion
Cerebral Cortex or Neocortex
- Different lobes for specific functions:
- Frontal lobe: planning and judgement
- Occipital lobe: vision
Nervous system two primary cell types
- Glia
- Neurons
Glia
- Support cells
- Wrap around axons thereby enhancing propagation of electrical signals
- BBB
- Take up and release ions and neurotransmitters
- Ex: excess glutamate released at synapses that is not degrdaded or transported back into the presynaptic terminal is taken up by astrocytes
- Oligendrites:
- form myelin sheaths around axons in the CNS
- Schwann cells:
- Found in peripheral nervous system, form meylin sheaths around nerons at regular intervals
- Astrocytes:
- Make contact with blood capillaries and neurons and thereby are part of the BBB. Also have a nutritive role. Also take up excess neurotramitters released from neurons
Neurons
- Many types of neurons that can be distinguished on the basis of morphology, location, and neurotransmitters released
- Ex: cell body of spinal motor neurons are in the spinal cord and send axonal projections long distances throughout the body to skeletal muscle
- Pyramidal neurons:
- Hippocampus
- Role in the foramtion of hippocampus-dependent memory; have up to a thousand synapses
- Purkinjee neurons
- Cerebellum
- Elaborate dendritic trees
- 80-100 billion neurons in the human brain and about 100 trillion synapses. Each neuron has an average of 500 synapses
- Lots of capacity to process and store information
Neurons are polarized cells
- Signalling cells that reieve and send messaged
- Signals recieved at dendrites and sent from opposing end (axon)
- Parts to a neuron:
- Cell body, axons, and dendrites
- Dendrites meeting axons is a synapse
Detailed View of Neuron
- Axoplasmic transport where molecules go from the cell body to axon terminals
- Dendrites have mRNA and can carryout dendritic protein synthesis
Signaling with neurons is electrical
- The neuronal plasma membrane contains pumps and exchange proteins that produce ionic gradients across the membrane
- These ion gradients result in an electrical potential across the membrane.
- Transient changes in membrane potential are used to signal within the neuron.
- These changes are often initiated by the opening of neurotransmitter-gated ion channels, which allow ions to flow down their concentration gradient, thus disrupting the resting membrane potential.
- If the membrane potential reaches a threshold value, voltage-gated channels in the membrane open generating an action potential…… a large, rapid, self-correcting flux in membrane potential.
- Action potentials propagate toward the axon terminal where they cause voltage-gated calcium channels to open. Influx of calcium into the axon terminal triggers the release of chemical messengers called neurotransmitters.
Signaling between neurons (neurotransmission) is chemical
- mediated by the tightly regulated secretion of neurotransmitters.
- Neurotransmitters are secreted at synapses
- Chemical signaling between neurons is referred to as neurotransmission or synaptic transmission.
- Drugs that affect neurotransmission constitute the majority of psychotropic reagents
- important to know the molecular events that produce and regulate neurotransmission
- The tightly regulated membrane trafficking cycle that mediates the secretion of transmitter, the diffusion of neurotransmitter across the synaptic cleft (the space between axon and dendrite) and the interaction of neurotransmitter with specific receptors on the post-synaptic membrane are illustrated below.
- Each is a potential site of drug action.
Stages of neurotransmission
- synthesis of transmitter occurs in the presynaptic terminal, i.e. the enzymes required for transmitter synthesis are present at the synapse
- transport of transmitter into synaptic vesicles is accomplished by specific transporter proteins in the vesicle membrane. Synaptic vesicles are assembled in endosomal structures.
- targeting of vesicles to a specialized region of the presynaptic membrane that is directly opposite the post-synaptic receptors.
- priming of the vesicles for fusion. Targeting and priming are mediated by the formation and disassembly of protein complexes.
- depolarization of the presynaptic membrane by an action potential induces the opening of voltage- gated calcium channels
- calcium-dependent fusion of the vesicles
- Diffusion of transmitter across the synaptic cleft
- Transmitter binds to and activates post-synaptic receptors. Neurotransmitter receptors can be classified by their mechanism of action.
- Transmitter-gated ion channel mediate fast neurotransmission
- G-protein coupled receptors initiate the production of secondary chemical messengers (second messengers). G-protein-coupled receptors mediate slower neurotransmission also called neuromodulation.
- Clearance of transmitter from the synapse. This is accomplished by two mechanisms:
- i. degradation of transmitter in the synapse by metabolic enzymes
- ii. reuptake of transmitter by transporter proteins on the plasma membrane
All of these stages are potential sites of drug action.
Amino Acid Neurotransmitter
- Amino acid neurotransmitters:
- mediate the majority of fast neurotransmission in the nervous system
- are used by the majority of the neurons in the nervous system
- mediate most fast, local neurotransmission
- can also mediate slow neurotransmission
Amino acid neurotransmitters can be classified on the basis of their action
- excitatory - increase the excitability of target neurons, i.e. activate receptors that depolarize the post- synaptic membrane
- inhibitory - decrease the excitability of target neurons, i.e. activate receptors that hyperpolarize the post- synaptic membrane- GABA and glycine
Glutamate and Aspartate are excitatory neurotransmitters
- The amino acid glutamate is the major excitatory neurotransmitter in the CNS. Aspartate is also an excitatory amino acid transmitter. However, it is less common than glutamate.
- Glutamate-secreting neurons are distributed throughout the brain and generally synapse onto neurons within the same structure, i.e. they mediate local neurotransmission.
- Glutamate is the product of general metabolism. Its synthesis is not regulated at the synapse.
- Glutamate is transported into synaptic vesicles by a specific glutamate transporter protein in the synaptic vesicle membrane.
- A unique class of reuptake transporters removes glutamate from the synapse.
Kainate non-NMDA channels
- Pass sodium
- Fast and common
AMPA Receptors
- Non-NMDA channels
- pass sodium
- display fast kinetics (opening, closing, desensitization)
- found at the majority of excitatory synapses where they mediate the majority of fast neurotransmission rapid desensitized.
NMDA-activated channels
pass sodium and calcium ,display complex regulation NMDA sensitive channels are activated by a combination of glutamate and membrane
depolarization. At normal membrane potentials magnesium sits in the pore of the channel blocking it. Membrane depolarization (for example resulting from the opening of AMPA channels) dislodges the magnesium, allowing sodium and calcium ions to pass. Therefore the NMDA receptor must both bind glutamate and be in a depolarized membrane to pass ions. These properties mean that NMDA receptors function as coincidence detectors (they detect the coincidence of glutamate and depolarization).
NMDA receptors in the hippocampus are activated during memory formation and initiate a chain of events that generate memory traces in the hippocampus. In contrast to AMPA receptors, which are activated during normal signaling during neurotransmission, NMDA receptors are only activated under very strong rapid signaling when the membrane depolarization through AMPA receptors is coincident with glutamate binding to NMDA receptors.
metabotropic receptors
There is one pharmacological class of glutamate receptor that acts through second messengers. These channels are sensitive to the drug quisqualate. Quisqualate-sensitive glutamate receptors are referred to as metabotropic glutamate receptors. They act through G coupling proteins.
Inhibitory amino acids: Gamma Amino Butyric Acid (GABA)
- GABA, a simple amino acid, is the major inhibitory transmitter in the CNS. GABA is derived from the decarboxylation of the amino acid glutamate. This reaction is catalyzed by the enzyme glutamic acid decarboxylase (GAD).
- There is cell-specific expression of GAD
The GABA synapse
- GABA is transported into synaptic vesicles by a specific vesicular GABA transporter. GABA is removed from the synapse by a high affinity re-uptake transporter.
- GABA Receptors - two major classes;
- GABA-gated chloride channels that mediate fast inhibitory neurotransmission. Opening of these chloride channels hyperpolarizes the post-synaptic membrane making it less likely to produce an action potential.
- metabotropic GABA receptors - G-protein coupled receptors that regulate potassium channels via changes in levels of the second messenger cAMP.
Acetylcholine (ACh)
Like the amino acid neurotransmitters, acetylcholine mediates both fast and slow neurotransmission. ACh is involved in a variety of nervous system functions, ranging from autonomic regulation of the peripheral nervous system, neuroendocrine activity, learning and memory, affect and motor functions. Loss of cholinergic neurons is a hallmark of Alzheimer’s disease suggesting that cholinergic neurotransmission has a central role in higher brain functioning.
Anatomy of cholinergic neurons
- While there are many cholinergic neurons in the brain, they are considerably fewer in number than neurons that secrete glutamate and GABA. Cholinergic neurons also have broader projections than do glutamate and GABA neurons. The major pathways are illustrated in this figure. They include:
- Neurons from the nucleus basalis project to cerebral cortex.
- 2.Neurons from those from medial septal and diagonal band project to hippocampus….pathways important for learning and memory which degenerate in Alzheimer’s disease.,,Acetylcholione esterase inhibitors are used to treat Alzheimer’s.
Biogenic Amines
The biogenic amines include:
the catecholamines dopamine, norepinephrine (and epinephrine) the indolamine serotonin
histamine
Biogenic amine transmitters mediate slow neurotransmission, i.e. act on G-protein-linked receptors. Drugs that act on amine neurotransmission are common in psychiatric medicine.
Dopamine (DA)
- Dopamine neurotransmission plays a role in:
- motor control - deficiencies in dopamine neurotransmission are associated with Parkinson’s disease, Huntington’s chorea, and Gilles de la Tourette syndrome
- sexual behavior - increases in central dopamine activity produce increased sexual behavior. DA agonists, such as apomorphine enhance, and antagonists, such as haloperidol, decrease the frequency of mounting behavior in rats, suggesting that DA is also involved in regulating sexual function
- Reward
- the action of anti-psychotic drugs. (This suggests that dopamine plays a role in normal mentation.)
Dopaminergic pathways
- Neurons synthesizing DA in two regions: the midbrain containing the substantia nigra and the adjacent ventral tegmental area and the hypothalamus.
- Nigrostriatal projections go to the striatum and control posture and movement, they degenerate in Parkinson’s.
- Ventral tegmental extend to the cortex and limbic system, important for targeted oriented behaviors including psychotic behavior.
- Those projecting form the ventral tegmental to the nucleus accumbens are believed to be involved in addiction.
- DA synthesized in the arcuate extend to the pituitary
Dopamine synapse
- The Dopamine reuptake transporter is a member of a family of transporters that includes the GABA, norepinephrine and serotonin reuptake transporters. These transporters are the site of action of many psychoactive drugs and are discussed in more detail in the lecture on stimulants.
- Dopamine receptors are divided into several classes based on their sensitivity to pharmacological agents.
Norepinephrine (NE)
Neurotransmission mediated by norepinephrine plays a role in:
Affect (an expressed or observed emotional response) – tricyclic anti-depressants alter NE neurotransmission
attention - drugs that increase NE neurotransmission increase attention and focus.
Noradrenergic Pathways
Norepinephrine-secreting neurons are present in two structures
the locus ceruleus (in pons) with projections to the cortex, thalamus and olfactory bulb
the lateral tegmental system (in brain stem) with projections to the amygdala, cerebellum, and spinal cord
Serotonin (5-HydroxyTryptamine)
Serotonergic neurotransmission is important in the control of:
affect - The most common anti-depressants alter serotonergic neurotransmission.
sleep - Blockade of serotonin biosynthesis causes marked insomnia in experimental animals.
For a number of years, the amino acid tryptophan, the precursor of serotonin, was used as a mild sedative agent. While tryptophan is no longer available for this purpose in the U.S.A. (a tryptophan contaminant caused serious side effects in some people), another serotonin derivative, melatonin, is now being used as a sedative agent.
appetite – Increased serotonin levels decrease appetite.
sexual behavior - Decreasing brain serotonin increases sexual behavior in rats - both heterosexual- and homosexual- while increasing brain serotonin levels decrease it.
Serotonin Metabolism
- The pathway of serotonin synthesis is shown here. The initial step in the biosynthesis of serotonin involves the ring hydroxylation of tryptophan. This is the rate-limiting step in the pathway.
- Serotonin is degraded by monoamine oxidase (MAO).
- Serotonin is also the precursor of melatonin, a hormone synthesized in the pineal gland which is thought to regulate entrainment of your circadian rhythm.
Anatomy of serotonergic projections
Serotonergic neurons are found in the raphe (ra phe) nuclei in both midbrain (rostral raphe) and brain stem (caudal raphe). These neurons have very broad projections to thalamic, limbic and cortical regions.
Note the projections to the spinal cord from the caudal raphe nucleus. This projection may be involved in the increased pain perception observed in depressed (low serotonergic) individuals.
Serotonin Synapse
Serotonin receptors fall into seven classes which will be discussed in subsequent lectures.
Most of the 5HT receptors are G-protein coupled receptors and so mediate slow neurotransmission through second messenger generation
Serotonin receptors are differentially localized in the brain
Different serotonin receptors are the site of action of different drugs.
Histamine neurotransmission is involved in:
- arousal - increased histamine increases wakefulness, decreased histamine increases slow wave sleep
- motor behavior, eating/drinking, sexual behavior - these actions may be indirect and may reflect histamine effects on catecholaminergic neurons
- metabolism - histamine is synthesized from histidine, an amino acid present in all cells, by the enzyme histidine decarboxylase.
Anatomy of histamine neurons
- Amine secreting neurons are found in the TM (tuberomammillary) nucleus of the hypothalamus. These neurons have very broad projections suggesting that histamine is a primary neurotransmitter in hypothalamic regulation of brain function.
- Histamine receptors are found throughout the brain and are also present on glia and blood vessels.
- H1 - coupled to Gq, which activates phospholipase C
- H2 - activate Gs which increases cAMP production
Neuropeptides
- In addition to classical neurotransmitters, neurons also communicate by releasing peptide transmitters. Many neuro-active peptides have been characterized. Peptides are thought to act in concert with other transmitters - i.e. neurons that release neuropeptides often release a classical neurotransmitter in addition to a peptide.
- The action of peptides is generally modulatory. Neuropeptides regulate many complex functions and behaviors including reproduction, eating, and mood.
- Neuropeptides are small proteins that are often synthesized as larger precursor peptides, which are proteolyzed to produce shorter, biologically active peptides.
- Neuropeptides are secreted via a different mechanism than standard neurotransmitters. Rather than being secreted from small vesicles assembled and filled at the synapse, peptides are released from large, Golgi-derived vesicles that do not cluster over active zones in presynaptic terminals. Much less is known about the regulation of peptide release than the release of standard neurotransmitters.
- Most neuropeptide receptors, of which the opiate receptors are the best characterized, are G-protein coupled receptors.
