Introduction to Neuroscience PDF - Regis University Spring 2025

Introduction to Neuroscience RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Readings & References Dan Berlau, PhD Requ...

Introduction to Neuroscience RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Readings & References Dan Berlau, PhD Required [email protected] Integrated Pharmacotherapy 3 Introduction to Neuroscience course notes (this document) Integrated Pharmacotherapy 1 Drug Receptors: Biochemistry & Pharmacology Integrated Pharmacotherapy 1 Principles of Pharmacodynamics and SAR Optional "Chapter 451: Biology of Psychiatric Disorders" Harrison's Principles of Internal Medicine, 21st edition from Access Pharmacy. Learning Objectives for the RAT 1. Provide definitions for all terms highlighted in bold text. 2. Locate and name the four major lobes of the cerebral cortex when given an unlabeled image of the human brain. 3. Explain the functioning of the major areas of the brain. 4. Define the blood-brain barrier and describe mechanisms that regulate the movement of molecules between the circulation and the extracellular fluid of the central nervous system. 5. Compare and contrast the central nervous system and the peripheral nervous system. 6. Explain the differences between projection neurons and interneurons. 7. List the types of glial cells and what their primary functions are. 8. Identify the major parts of a typical neuron and explain what their functions are. 9. List and describe the key steps in the neurophysiological funtion of neurons. 10. Identify regulatory mechanisms in the normal brain that control the sequential excitation of neuronal networks, including the influence of neurotransmitters, ions, channels, and receptors. 11. Identify the direction of movement of sodium, calcium, chloride, or potassium ions across a neuronal cell membrane that promotes excitation (depolarization) or inhibition (hyperpolarization). 12. Given a membrane potential value in millivolts (mV), compare to the normal resting potential of a typical neuron. 13. List and characterize the major ion channels and ligands that are associated with neuronal excitatory or inhibitory potentials. 14. List and characterize the neurotransmitter receptor types that are associated with modulating neuronal excitation. 15. Explain how the threshold potential of a neuronal membrane is related to the likelihood of generating an action potential in a neuron. 16. Describe the different ways that neural networks are formed/maintained including neuronal development, synaptic plasticity, and summation. 17. Review previous IP notes (see above) for a refresher on the structure and function of neurotransmitter receptors. OVERVIEW OF THE NERVOUS SYSTEM Neuroscience is a dynamic and multidisciplinary field that unravels the intricacies of the nervous system, the body's command center. As pharmacy students embark on their academic journey, understanding the fundamental structure and function of the nervous system is essential. This section provides an in-depth exploration of the central nervous system (CNS) and peripheral nervous system (PNS), elucidating the roles of the brain, spinal cord, and peripheral nerves in orchestrating physiological processes. MACROANATOMY & PHYSIOLOGY Brain Areas Figure 1. Major areas of the brain (midsagittal view) The human brain consists of various regions that contribute to the orchestration of cognition, emotions, and physiological functions. Understanding the key brain areas is essential for gaining insights into neurological disorders, drug actions, and overall brain function. This summary provides a concise overview of some of the crucial human brain areas (Figure 1). Cerebral Cortex The cerebral cortex is the outermost surface of the brain and is also the newest evolved area in humans. Performing a large variety of functions, it is divided into four major areas (lobes). Frontal Lobe: Executive Control Center Situated at the front of the brain, the frontal lobe is the epicenter of executive functions. Responsible for decision-making, problem- solving, and emotional regulation, this region plays a pivotal role in personality and social behavior. The prefrontal cortex, a subsection of the frontal lobe, is particularly critical for high-order cognitive processes and is susceptible to developmental changes and environmental influences. Temporal Lobe: Center of Memory and Auditory Processing Nestled on the sides of the brain (at the temples), the temporal lobes are involved in auditory processing, language comprehension, and memory formation. Dysfunction in this region can lead to memory disorders and auditory processing deficits. Parietal Lobe: Integrating Sensory Information The parietal lobe integrates sensory information from various modalities, facilitating spatial awareness, perception of stimuli, and coordination of movements. The somatosensory cortex, located in the parietal lobe, receives and processes tactile information, allowing individuals to perceive sensations such as touch and temperature. Occipital Lobe: Visual Processing Center The occipital lobe, positioned at the back of the brain, is primarily responsible for visual processing. The primary visual cortex interprets visual stimuli received from the eyes, allowing for the perception of color, shape, and motion. Disorders in this area can result in visual impairments and disturbances. Limbic System Including structures like the amygdala, hippocampus, and hypothalamus, the limbic system is intricately involved in emotions, memory formation, and the regulation of the autonomic nervous system. The hippocampus is believed to be the primary memory processing center, helping short-term memories transfer into long-term memories. The amygdala plays a central role in the processing of emotional responses and the formation of emotional memories. Integrated Pharmacotherapy 3 2 Introduction to Neuroscience Basal Ganglia The basal ganglia, situated deep within the brain, are crucial for motor control, procedural learning, and habit formation. Dysfunction in this region is associated with movement disorders such as Parkinson's disease and Huntington's disease. Brainstem Connecting the brain to the spinal cord, the brainstem regulates essential autonomic functions, including breathing, heartbeat, and basic survival instincts. The medulla oblongata, pons, and midbrain are integral components, ensuring the body's homeostasis and responsiveness to external stimuli. Cerebellum Positioned at the back of the brain, the cerebellum is essential for coordination, balance, and motor learning. It receives information about ongoing movements and fine-tunes motor responses, contributing to precise and controlled actions. Corpus Callosum The corpus callosum, a dense bundle of nerve fibers, connects the brain's hemispheres, allowing for communication and integration of information between the left and right sides. This structure is critical for various cognitive processes, including language, problem- solving, and sensory integration. Blood Brain Barrier The blood-brain barrier (BBB) is a highly specialized and intricate system that safeguards the delicate environment of the brain. This dynamic interface, formed by endothelial cells, tight junctions, and specialized transporters, serves as a selective barrier, tightly regulating the passage of substances between the bloodstream and the brain tissue. P-Glycoproteins in the BBB Structure and Composition The BBB is primarily composed of endothelial cells that line the capillaries in Amino acids, peptides, and many drugs must be the brain. These endothelial cells are distinct from those found in other tissues, transported through the vessel wall via bidirectional possessing tight junctions that significantly restrict the movement of molecules transport proteins on the luminal surface. Once inside the endothelial cell, however, many drugs are quickly (Figure 2). Adjacent astrocytes (described below), along with pericytes, further exported back into the blood through the activity of contribute to the structural integrity of the BBB. Together, they form a formidable efflux proteins such as P-glycoprotein and organic defense against unwanted substances trying to enter the brain. acid transport protein. The function of efflux proteins is to protect the CNS from toxic substances, and these proteins account for the limited central effects of many Tight Junctions and Selective Permeability drugs including baclofen, digoxin, vinca alkaloids, Tight junctions between endothelial cells are crucial components of the BBB, cyclosporine A, etc. Upregulation of efflux proteins may creating a seal that prevents the free diffusion of molecules between cells. This result in increased resistance to the effects of medica- selective permeability ensures that only essential nutrients and molecules vital for tions. brain function, such as oxygen and glucose, can pass through. Small lipophilic molecules, like oxygen and carbon dioxide, can traverse the BBB through passive diffusion, while larger or hydrophilic substances require specialized transport mechanisms. Figure 2. Crross section of a cerebral blood vessel showing the BBB Transport Mechanisms The BBB employs several transporters to facilitate the entry of essential nutrients and maintain the homeostasis of the brain. Glucose transporters, amino acid transporters, and specific receptors for hormones are strategically placed to allow the passage of necessary substances. Active transport mechanisms, such as efflux pumps, actively pump out potentially harmful compounds, preventing them from accumulating in the brain. Functions of the Blood-Brain Barrier The BBB serves multifaceted roles, acting as a protective shield, regulator, and gatekeeper for the brain. It protects the central nervous system from pathogens, toxins, and fluctuations in blood composition that could disturb the neural environment. Moreover, it maintains a stable Integrated Pharmacotherapy 3 3 Introduction to Neuroscience environment by tightly controlling ion concentrations, Figure 3. Major nerves of the PNS preventing sudden shifts that could impair neural function. While the BBB is a vital protective mechanism, it poses challenges for drug delivery to the brain. Many therapeutic agents, including certain drugs and antibodies, struggle to cross the BBB due to its selective permeability. This limitation complicates the treatment of various neurological disorders, necessitating innovative approaches such as nanoparticle formulations or the development of specific transport mechanisms. Disruptions in the BBB are implicated in various neurological conditions. Injuries, infections, and certain diseases can compromise the integrity of the BBB, allowing harmful substances to enter the brain and potentially contribute to inflammation or neurodegeneration. Understanding these pathological changes is crucial for developing targeted interventions to restore BBB function and mitigate the progression of neurological disorders. Peripheral Nervous System The peripheral nervous system (PNS) is a complex network of nerves that extends beyond the spinal cord and brain, connecting various organs, muscles, and tissues to the central nervous system. Including both sensory and motor neurons, the PNS plays a crucial role in facilitating communication between the body and the central nervous system. Sensory neurons transmit signals from sensory organs to the brain, enabling the perception of external stimuli like touch, temperature, and pain. Motor neurons, on the other hand, convey instructions from the brain to muscles and glands, orchestrating voluntary and involuntary movements as well as physiological responses. The PNS further divides into the somatic nervous system, governing voluntary muscle movements, and the autonomic nervous system, regulating involuntary functions like heart rate, digestion, and respiratory rate. The latter subdivides into the sympathetic and parasympathetic divisions, working in tandem to maintain homeostasis. Overall, the PNS plays a pivotal role in ensuring seamless communication between the body and the central nervous system, contributing to the integration and coordination of various physiological processes. Feel free to review your IP 2 Hypertension Part I notes regarding the sympathetic and parasympathetic divisions of the PNS. NEURONAL ANATOMY AND PHYSIOLOGY Types of Neurons Projection Neurons Projection neurons, also known as principal or output neurons, are characterized by their long axons that extend over significant distances, connecting different regions of the nervous system (Figure 5 on page 5). These neurons play a fundamental role in transmitting information between distinct brain regions. For example, pyramidal neurons in the cerebral cortex are projection neurons that send signals to other cortical areas or subcortical structures. The axons of projection neurons often form complex pathways, Integrated Pharmacotherapy 3 4 Introduction to Neuroscience  Figure 5. Images of neurons on both cartoon form (left) and artifically highlighted true image (right) facilitating the integration and transmission of signals across various brain regions. Their crucial role in long-range communication makes projection neurons essential for coordinating higher-order cognitive functions and motor activities. Interneurons In contrast, interneurons are local circuit neurons primarily confined to specific brain regions. They facilitate communication between neighboring neurons and are crucial for local processing and modulation of neural activity. Interneurons exert inhibitory or excitatory effects on nearby neurons, contributing to the fine-tuning of neural circuits. GABAergic and glutamatergic interneurons are examples of inhibitory and excitatory interneurons, respectively. By regulating the balance of excitation and inhibition, interneurons play a pivotal role in shaping the overall activity patterns within a given brain region. Their intricate connections and modulatory functions make interneurons essential for information processing, sensory integration, and maintaining overall neural network stability. Glial Cells Figure 6. Glial cells types Glial cells, once considered mere support cells, have emerged as essential players in the complex Radial Glia landscape of the nervous system. These non- Astrocyte neuronal cells constitute a diverse group, each type endowed with specialized functions crucial for maintaining neuronal health, synaptic activity, and overall brain homeostasis (Figure 6). Astrocytes Blood Vessel Astrocytes, the most abundant glial cells, are star-shaped structures that form an intricate network throughout the brain. Beyond providing structural support, astrocytes contribute Neuron significantly to neural function. They regulate the extracellular environment by maintaining ion balance, modulating neurotransmitter levels, and participating in the blood-brain barrier Oligodendrocytes formation. Moreover, astrocytes play a vital role in synaptic plasticity, influencing learning and Microglia memory processes. Recent research also suggests their involvement in information processing, Ependymal Cells challenging the traditional view of neurons as the sole contributors to cognitive functions. The image above shows the variety of glial cells and how they interact with neurons in the brain. Created by Rose Brehon, Class 2024. Oligodendrocytes and Schwann Cells Oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) share a common mission: to insulate axons with myelin sheaths. This fatty substance enhances the speed and efficiency of electrical signal conduction along axons. Oligodendrocytes myelinate multiple axons, while Schwann cells envelop a single axon. Dysfunction in these glial cells can lead to demyelinating diseases such as multiple sclerosis, underscoring their critical role in maintaining proper neural conductivity. Integrated Pharmacotherapy 3 5 Introduction to Neuroscience Microglia Microglia are the resident immune cells of the central nervous system, tirelessly patrolling for signs of injury, infection, or abnormal cellular activity. Upon detecting such disturbances, microglia become activated, assuming various roles. They phagocytose debris, release inflammatory mediators, and contribute to the resolution of neural damage. Dysregulation in microglial activity has been implicated in neuroinflammatory conditions and neurodegenerative diseases, highlighting their crucial role in maintaining a balanced immune response within the brain. Ependymal Cells Ependymal cells line the ventricles of the brain and the central canal of the spinal cord, forming a barrier between neural tissue and cerebrospinal fluid (CSF). These cells contribute to the production and circulation of CSF, playing a vital role in maintaining the brain's buoyancy, protecting against mechanical damage, and facilitating the removal of waste products. Ependymal cells also contribute to the regulation of neural stem cells in certain regions, hinting at their involvement in neurogenesis. Radial Glia During embryonic development, radial glial cells serve as scaffolds for migrating neurons, guiding them to their appropriate locations in the developing brain. While considered a transient cell type, recent research suggests that radial glia may persist into adulthood and contribute to neurogenesis and neural repair in specific brain regions. Parts of the Neuron Neurons, the fundamental building blocks of Figure 7. The major parts of a neuron the nervous system, are intricate cells designed for the transmission of electrochemical signals (Figure 7). Comprising distinct components, each with specialized functions, neurons play a pivotal role in information processing, integration, and communication within the complex neural networks of the body. Cell Body (Soma) At the core of every neuron lies the cell body or soma, akin to the headquarters directing the neuron's operations. It houses the nucleus, the cellular command center containing genetic material that dictates the neuron's characteristics and functions. The cell body integrates signals received from dendrites and initiates the generation of action potentials, the electrical impulses that propel information along the neuron. Dendrites Dendrites extend from the cell body, resembling tree branches, and serve as the primary receivers of incoming signals from neighboring neurons. These structures are covered with synapses, specialized junctions where neurotransmitters facilitate communication between neurons. The complex branching patterns of dendrites enable the neuron to receive and process a multitude of signals simultaneously, providing the foundation for information integration. Axon The axon is a long, slender projection that extends from the cell body, serving as the primary transmission line for electrical impulses. Wrapped in a fatty substance called myelin (see below), the axon facilitates the rapid conduction of signals, ensuring swift and efficient communication. Nodes of Ranvier, gaps in the myelin sheath, play a crucial role in this process by allowing the action potential to jump from one node to the next, accelerating signal transmission. Axon Terminals At the end of the axon, terminal branches form synaptic terminals or axon terminals, establishing connections with dendrites or cell bodies of other neurons. The synapse is the site where neurotransmitters are released from the axon terminal, traversing the synaptic cleft to bind with receptors on the target neuron's dendrites. This process ensures the continuation of the signal from one neuron to the next, facilitating communication within neural circuits. Integrated Pharmacotherapy 3 6 Introduction to Neuroscience Myelin Sheath The myelin sheath, produced by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, wraps around the axon, providing insulation. This insulation enhances the speed of signal transmission, as the action potential can jump between nodes of Ranvier, reducing the energy and time required for the signal to travel along the axon. NEUROPHYSIOLOGY Neurons work through a complex process of electrical and chemical signaling, facilitating communication within the nervous system. The key steps involved in this process are: Resting Potential Neurons maintain a resting membrane potential by establishing a charge differential or ion gradient across the plasma membrane. The resting potential is negative because the concentrations of the positively charged ions sodium (Na+) and calcium (Ca2+) are higher outside of the cell than inside. Minor contributions to the resting potential are made by negatively charged intracellular proteins and chloride (Cl-) and are balanced by the potassium (K+) gradient. At a normal resting negative potential of -70 millivolts (mV), a neuronal cell is said to be polarized. To maintain this resting potential, a Na+/K+ pump constantly pumps Na+ out of the cell in exchange for pumping K+ into the cell. This requires ATP and is one of the primary reasons that the brain requires so much energy to function. Depolarization Neurons are excitable, which means that the resting potential can be reversed by inducing the activity of ion channels on the cell surface. Regulation of ion channel activity occurs by two primary mechanisms: ligand-gating and voltage-gating. A ligand-gated channel opens in response to the binding of an extracellular agonist and allows particular ions to pass through the cell membrane. The most common excitatory ligand is glutamate, which activates a variety of receptors and ion channels including the NMDA and AMPA- type glutamatergic cation channels. As cation channels open and allow Na+ or Ca2+ to enter the cell, the membrane potential becomes less negative and approaches the threshold at which the cell is triggered to generate an action potential. The action potential is a wave of electrical activity generated by a substantial influx of Na+ (or occasionally Ca2+) through voltage-gated channels. Voltage-gated Sodium Channels Voltage-gated Na+ channels are critical for the initiation and propagation of action potentials in excitable cells, such as neurons and muscle fibers. These channels are embedded in the plasma membrane and are activated by changes in membrane potential. When a neuron receives a sufficient depolarizing stimulus, the membrane potential reaches a threshold, triggering the opening of voltage-gated Na+ channels. This allows Na+ ions to flow rapidly into the cell down their electrochemical gradient. The influx of positively charged Na+ ions causes further depolarization, creating the rising phase of the action potential. This positive feedback mechanism ensures that the action potential is an all-or-none event, propagating efficiently along the axon. As the membrane potential becomes more positive, the voltage-gated Na+ channels begin to close, ending the rapid influx of Na+. This closure is critical for the action potential's peak and for allowing the next phase, repolarization, to occur. The channels' swift activation and subsequent closure ensure the rapid and transient nature of the action potential, allowing neurons to transmit information quickly and precisely. Without functional voltage-gated Na+ channels, action potentials would fail to propagate, disrupting neural communication and muscle contraction. Figure 8. Inactivation of the voltage-gated sodium channel Mechanism of the Inactivation Gate The inactivation gate of the voltage-gated Na+ channel is a crucial structural feature that ensures the unidirectional flow and transient nature of action potentials (Figure 8). Unlike the activation gate, which opens in response to depolarization, the inactivation gate closes the channel after a brief period, even if the membrane remains depolarized. This "ball-and-chain" mechanism involves a specific part of the channel protein that physically blocks the Na+ channel pore from the inside. The inactivation gate is triggered by the same depolarization that opens the activation gate but operates on a slightly delayed timeline. This delay allows for the rapid influx of Na+ to initiate the action potential before the channel is closed. Integrated Pharmacotherapy 3 7 Introduction to Neuroscience The inactivation gate ensures that the Na+ channels remain inactive until the membrane potential returns to its resting state during repolarization. Once the membrane potential is restored, the inactivation gate reopens, allowing the channel to return to its closed, activatable state. This refractory period prevents the immediate reactivation of the channel, ensuring that action potentials propagate in a unidirectional manner along the axon. The coordination between the activation and inactivation gates is essential for the proper timing and fidelity of neural signaling. Disruptions in this mechanism, such as mutations affecting the inactivation gate, can lead to pathological conditions like epilepsy or cardiac arrhythmias. Action Potential The influx of sodium ions generates an action potential (Figure 9), a brief electrical impulse that travels along the neuron's axon. This is a rapid change from a negative to a positive membrane potential. Voltage-gated channels open in response to a change in the electrical potential of the membrane. Neuronal sodium channels, for example, open when the membrane is depolarized to -55 mV, either by the spontaneous opening of other channels (such as the T-type calcium channel) or the activity of ligand-gated or voltage-gated channels nearby. Figure 9. Steps of an action potential An action potential is all-or-none, meaning that once the threshold is reached, an action potential will occur. There are not different sizes/ gradations of action potentials, they simply occur, or do not, depending on if threshold is reached or not. Depolarization also increases the flow of K+ ions. Potassium, in a resting neuron, is more concentrated inside the cell than outside. When the membrane is depolarized, voltage-gated K+ channels open, allowing K+ to rush out of the cell, which helps to repolarize the membrane. The action potential travels down the axon due to the opening and closing of voltage-gated ion channels along its length. This ensures the unidirectional transmission of signals. Saltatory Conduction In myelinated axons, the transmission of an action potential seems to "jump" from each Node of Ranvier to the next. This is known as saltatory conduction from the Latin saltus which means "to jump". This is because the myelin sheath completely wraps the axon and does not allow for any ion transfer at all. Thus, under the myelin, instead of action potentials, the neuron uses graded potentials. Because of the high resistance of the myelin, the graded potential is significantly faster than the action potential with one major caveat. It degrades as it moves along the axon. This degradation is in contrast to the action potential, which is self-propagating and doesn't degrade. The Nodes of Ranvier are spaced along the axon so that as the signal is degrading, it has just enough depolarization to meet threshold at the next node. Therefore, in a myelinated axon, the neuron switches from action potential (at the Nodes of Ranvier) to graded potential (under the myelin sheath). Axon Terminals and Synaptic Transmission The movement of an action potential (depolarization) through a neuron eventually leads to the axon terminal, where the neuron synapses with another. This depolarization activates voltage-gated Ca2+ channels, allowing Ca2+ to enter the neuron. This Ca2+ acts as a signal to cause the cell to release neurotransmitters into the synaptic space between the axon terminal and adjacent neurons as seen in Figure 10 on page 9. Reuptake and Termination After neurotransmitters transmit their message across the synaptic cleft, reuptake mechanisms swiftly recycle them back into the presynaptic neuron. Specialized proteins, like transporters, actively transport neurotransmitters from the synaptic cleft into the presynaptic neuron, terminating their action. This reuptake process ensures the timely cessation of neurotransmitter signaling, preventing excessive activation of postsynaptic receptors and allowing for precise control over neuronal activity. Dysregulation of neurotransmitter reuptake can lead to various neurological disorders, making it a critical target for pharmacological interventions. Postsynaptic Potentials If the cell makes synaptic connections to inhibitory interneurons, these interneurons will suppress the activity of adjacent cells in nearby networks after the action potential has passed. Most inhibitory synapses utilize the neurotransmitter γ-aminobutyric acid (GABA). GABA exerts effects on neuronal activity through two different types of receptors, GABAA and GABAB. GABAA receptors are chloride channels that permit the passage of Cl- anions into the cell, causing an electrical hyperpolarization of the membrane. Integrated Pharmacotherapy 3 8 Introduction to Neuroscience  Figure 10. Neurotransmission across the synapse GABAB receptors can also cause hyperpolarization, Figure 11. Interaction of excitatory and inhibitory synapses. but are much slower and long lasting, as they use G protein signaling to activate cellular changes. A hyperpolarized cell is less likely to become activated by an excitatory input because its electrochemical gradient is even more negative than the resting state (Figure 11). An inhibitory (I) signaling pathway hyperpolarizes the membrane through generating an inhibitory post-synaptic potential (IPSP). Excitatory interneurons can release neurotransmitters that can slightly depolarize the membrane, leading to an excitatory post-synaptic potential (EPSP). Several other modulatory neurotransmitters can also control the frequency and amplitude of network firing. These neurotransmitters (dopamine, serotonin, adenosine) commonly signal via G protein-coupled receptors rather than ion channels, and their effects are less dramatic than glutamate or GABA. Interaction of excitatory and inhibitory synapses. On the left, a suprathreshold stimulus is given to an excitatory pathway (E) and an action potential is evoked. On the right, this same stimulus is given shortly after activating an inhibitory pathway (I), which results in an inhibitory postsynaptic potential (IPSP) that prevents the excitatory potential from reaching threshold. NEUROTRANSMITTERS Excitatory and inhibitory neurotransmitters play opposing roles in neuronal signaling but are crucial for maintaining balance and coordination within the nervous system. Excitatory neurotransmitters promote neuronal activity by depolarizing the postsynaptic membrane, making it more likely for an action potential to occur. They achieve this by increasing the permeability of the postsynaptic membrane to Na+ ions or decreasing permeability to K+ ions, leading to depolarization and excitatory postsynaptic potentials (EPSPs). Integrated Pharmacotherapy 3 9 Introduction to Neuroscience In contrast, inhibitory neurotransmitters decrease neuronal activity by Endogenous vs. Exogenous Ligands hyperpolarizing the postsynaptic membrane, making it less likely for an action potential to be generated. They achieve this by increasing permeability to Cl- ions or Muscarinic and nicotinic receptors are named as such K+ ions, leading to hyperpolarization and inhibitory postsynaptic potentials (IPSPs). because they bind very specifically to muscarine and nicotine, respectively. They also bind to acetylcholine While excitatory neurotransmitters promote neuronal firing and signal propagation, readily, however. There is normally no muscarine or inhibitory neurotransmitters suppress excessive neuronal activity, maintaining a nicotine in the body or brain (unless someone smokes/ consumes a source). Under normal conditions, these delicate balance essential for proper brain function. Dysfunction in the balance receptors bind to acetylcholine only. Thus, for these between excitatory and inhibitory neurotransmission can lead to neurological receptors, their endogenous ligand is acetylcholine, disorders such as epilepsy, anxiety, and schizophrenia. Therefore, understanding the whereas their exogenous ligands are muscarine and mechanisms and differences between excitatory and inhibitory neurotransmitters nicotine. is crucial for developing effective pharmacological interventions targeting these systems. Excitatory Neurotransmitters Glutamate Glutamate, a primary excitatory neurotransmitter in the brain, plays a pivotal role in neural communication and synaptic plasticity. Abundant in the central nervous system, it stimulates postsynaptic neurons, influencing learning, memory, and cognitive functions. Glutamate operates through various receptor types, including AMPA, NMDA, and metabotropic receptors, regulating synaptic strength and transmission. While essential for normal brain function, excessive glutamate release can lead to excitotoxicity, implicated in neurodegenerative disorders. Balancing glutamatergic signaling is crucial for maintaining optimal neural function and preventing pathological conditions within the intricate network of the brain. Acetylcholine Acetylcholine contributes to various physiological functions, including memory, attention, and muscle control. Produced by cholinergic neurons, it acts on both muscarinic and nicotinic receptors. In the central nervous system, acetylcholine plays a key role in cognitive processes, and its deficits are linked to conditions like Alzheimer's disease. In the peripheral nervous system, it transmits signals to muscles, influencing movement and coordination. Striking a delicate balance in acetylcholine levels is essential for maintaining optimal neural and muscular function, impacting both cognitive and motor aspects of human physiology. Inhibitory Neurotransmitters GABA Gamma-aminobutyric acid or γ-aminobutyric acid (GABA) regulates neural excitability. GABA binds to GABA receptors, promoting inhibitory effects that counterbalance excitatory neurotransmitters. This modulation is crucial for maintaining neural stability, preventing overstimulation, and regulating anxiety. GABAergic dysfunction is associated with various neurological and psychiatric disorders, including anxiety disorders and epilepsy. Understanding the role of GABA in synaptic transmission is pivotal for unraveling mechanisms underlying brain function and for developing targeted interventions to address imbalances contributing to diverse neurological conditions. Neuromodulators A neuromodulator is a type of signaling molecule in the nervous system that doesn't directly cause excitation or inhibition like neurotransmitters do but rather modulates the activity of neurons and neural circuits, often over longer time scales. Unlike neurotransmitters, which act quickly at specific synapses, neuromodulators diffuse more widely and can affect multiple neurons or brain regions simultaneously. Neuromodulators can have diverse functions, including altering synaptic strength, influencing neuronal excitability, regulating neurotransmitter release, and modulating neural plasticity and network dynamics. Examples of neuromodulators include serotonin, dopamine, norepinephrine, and even acetylcholine. These molecules play essential roles in regulating various brain functions such as mood, motivation, attention, learning, memory, and pain perception. Dysregulation of neuromodulatory systems is implicated in numerous neurological and psychiatric disorders, making them important targets for pharmacological interventions. Integrated Pharmacotherapy 3 10 Introduction to Neuroscience Monoamines Figure 12. Structure and synthesis of monoamine A monoamine neuromodulator refers to a class of neurotransmitters neurotransmitters that play a crucial role in modulating neural activity and regulating various physiological and behavioral processes in the brain. Monoamines are characterized by the presence of a single amine group in their chemical structure. Examples of monoamine neuromodulators include serotonin, dopamine, and norepinephrine (Figure 12). Unlike traditional neurotransmitters involved in rapid signal transmission, monoamine neuromodulators act more slowly and exert prolonged effects on neural circuits. These neurotransmitters contribute to mood regulation, arousal, attention, and other complex behaviors, making them key players in the modulation and fine-tuning of neural activity throughout the central nervous system. Dysregulation of monoamine systems has been implicated in various psychiatric disorders, such as depression, schizophrenia, and bipolar disorder. Serotonin Serotonin plays a vital role in mood regulation, sleep, appetite, sex drive, and emotional well-being in the brain. Produced in serotonergic neurons, it modulates neural circuits through interaction with serotonin receptors. Imbalances in serotonin levels are linked to mood disorders such as depression and anxiety. Medications that enhance serotonin signaling, such as selective serotonin reuptake inhibitors (SSRIs), are commonly used to treat these conditions. Serotonin's multifaceted influence on neural function highlights its significance in maintaining emotional and psychological equilibrium within the intricate network of the central nervous system. Dopamine Dopamine governs diverse cognitive and motor functions in the brain. Produced by dopaminergic neurons, it acts on dopamine receptors, influencing reward, motivation, and motor control. Dopamine's role in the brain's reward pathway underlies its impact on pleasure and reinforcement, contributing to addiction and motivation. Dysregulation of dopamine is implicated in various neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and addiction. Medications targeting dopamine pathways are utilized in treating these conditions, underscoring the neurotransmitter's central role in orchestrating complex behaviors and maintaining neural homeostasis. Norepinephrine Norepinephrine modulates arousal, attention, and stress responses in the brain. Produced by noradrenergic neurons, it influences diverse physiological processes through activation of adrenergic receptors. Norepinephrine's involvement in the sympathetic nervous system contributes to the "fight or flight" response. Dysregulation of its levels is associated with mood disorders, attention deficit hyperactivity disorder (ADHD), and conditions like post-traumatic stress disorder (PTSD). Medications that influence norepinephrine pathways are employed in treating these disorders, highlighting its significance in maintaining emotional balance and cognitive function within the intricate neural networks of the central nervous system. NEUROTRANSMITTER RECEPTORS Neurotransmitter receptors in the brain play a crucial role in communication between neurons, which is essential for various brain functions including cognition, emotion, and movement. These receptors are specialized proteins located on the surface of neurons and can bind to specific neurotransmitters released into the synaptic cleft. There are two main types of neurotransmitter receptors: ionotropic receptors and metabotropic receptors. Ionotropic receptors are directly linked to ion channels and when activated by neurotransmitter binding, they cause rapid changes in the neuron's membrane potential, leading to a fast excitatory or inhibitory response. Metabotropic receptors, on the other hand, are coupled to intracellular signaling pathways via G proteins. Activation of these receptors leads to slower but longer-lasting changes in neuronal function through the modulation of second messenger systems. Additionally, neurotransmitter receptors can be further classified into subtypes, each with unique properties and distribution patterns throughout the brain. Please refer to your notes from IP 1 Drug Receptors: Biochemistry & Pharmacology and IP 1 Principles of Pharmacodynamics and SAR to review what you learned about neurotransmitter receptors. Integrated Pharmacotherapy 3 11 Introduction to Neuroscience NEURAL NETWORKS AND PLASTICITY Neural networks are formed through the interconnectedness of neurons in the nervous system. The process involves the establishment and strengthening of synaptic connections between neurons, which allows for the transmission of information in the form of electrical impulses. Neuronal Development Neural networks begin to form during embryonic development through a process called neurogenesis. Neurons are generated from neural stem cells and migrate to their designated locations in the nervous system. Once in place, neurons extend their axons and dendrites to connect with other neurons. Outside of a few small brain areas, adult neurons are postmitotic, which signifies that they do not undergo mitosis. Therefore, there are ostensibly no new neurons formed in the adult brain. Synaptic Formation Synapses play a crucial role in neural network formation. Synaptic connections are initially sparse and are established through a process called synaptogenesis. This process involves the growth of axonal terminals towards target neurons and the formation of synaptic contacts. Initially, synaptic connections are weak and unstable. Growth of new synapses on a neuron is called sprouting, whereas the removal of extra synapses is called pruning. Figure 13. Examples of LTP and LTD in a glutamatergic synapse Synaptic Plasticity Once synaptic connections are established, they undergo a process known as synaptic plasticity, which refers to the ability of synapses to strengthen or weaken over time in response to activity. This process is crucial for learning and memory formation. There are two primary forms of synaptic plasticity. Long-Term Potentiation (LTP) LTP occurs when synaptic activity strengthens the connection between neurons. It involves an increase in the efficacy of synaptic transmission, usually in the form of receptor upregulation. (Figure 13). Long-Term Depression (LTD) LTD, on the other hand, weakens synaptic connections. It occurs when synaptic activity is reduced or inhibited, leading to a decrease in synaptic efficacy. Integrated Pharmacotherapy 3 12 Introduction to Neuroscience Temporal and Spatial Summation Figure 14. Temporal and spatial summation Temporal and spatial summation are mechanisms by which neurons integrate incoming signals to determine whether to generate an action potential. Temporal summation occurs when multiple signals from a single presynaptic neuron arrive at the postsynaptic neuron in rapid succession, within a short period of time. If the combined depolarizations are sufficient to reach the threshold for triggering an action potential, the postsynaptic neuron will fire. Spatial summation involves the integration of signals from multiple presynaptic neurons that are active simultaneously but located at different synapses on the postsynaptic neuron. If the combined effects of these signals result in depolarization sufficient to reach the threshold, an action potential will be generated. By combining temporal and spatial summation, neurons can process and integrate a variety of incoming signals, allowing for complex information processing and the formation of functional neural networks (Figure 14). SUMMARY AND CONCLUSION The nervous system is one of the most complex aspects of the human body, with the understanding of the brain still in its infancy. Nevertheless, increasing your understanding of brain anatomy, neuroanatomy, and neurophysiology will make it easier to describe both the pathophysiology of many diseases and the mechanisms of action of many medications. This unit was designed to elucidate the basics of how the nervous systems works. Throughout the IP curriculum, subsequent units will add to your knowledge of neurobiology in the context of specific disease states. Integrated Pharmacotherapy 3 13 Introduction to Neuroscience