This document provides an overview of neuroanatomy and the nervous system. It discusses the central nervous system including the brain and spinal cord, as well as the peripheral nervous system. Key areas of the brain such as the cerebral cortex, prefrontal cortex, hippocampus, amygdala, hypothalamus, cerebellum, and blood brain barrier are described. The document also covers neuronal cells and their organelles that are important for neuronal signaling and function.
This document provides an overview of neuroanatomy and the nervous system. It discusses the central nervous system including the brain and spinal cord, as well as the peripheral nervous system. Key areas of the brain such as the cerebral cortex, prefrontal cortex, hippocampus, amygdala, hypothalamus, cerebellum, and blood brain barrier are described. The document also covers neuronal cells and their organelles that are important for neuronal signaling and function.
This document provides an overview of neuroanatomy and the nervous system. It discusses the central nervous system including the brain and spinal cord, as well as the peripheral nervous system. Key areas of the brain such as the cerebral cortex, prefrontal cortex, hippocampus, amygdala, hypothalamus, cerebellum, and blood brain barrier are described. The document also covers neuronal cells and their organelles that are important for neuronal signaling and function.
This document provides an overview of neuroanatomy and the nervous system. It discusses the central nervous system including the brain and spinal cord, as well as the peripheral nervous system. Key areas of the brain such as the cerebral cortex, prefrontal cortex, hippocampus, amygdala, hypothalamus, cerebellum, and blood brain barrier are described. The document also covers neuronal cells and their organelles that are important for neuronal signaling and function.
The Nervous System • Central Nervous System • Brain • Spinal Cord • Peripheral Nervous System • Afferent and efferent system The Nervous System • Basis of what persons sense, do, feel, and think (sensory, behavioral, affective, and cognitive experiences and attributes). • Organ that perceives and affects the environment and integrates past and present. • Sensory systems - create an internal representation of the external world. A separate map is formed for each sensory modality. • Motor systems - enable persons to manipulate their environment and to influence others' behavior through communication Brain • Approximately 100,000,000,000 neurons (nerve cells) • Approximately 1,000,000,000,000 glial cells. • The basic unit is a neuron. Parts of the neuron • Soma, or cell body, which contains the nucleus • Dendrites, which are processes that extend from the cell body and receive signals from other neurons • Axon, which extends from the cell body and transmits signals to other neurons Cerebral Cortex • Made up of white matter and gray matter. • White matter - myelinated axons transporting impulses between the gray matter and lower brain structures. • Gray matter - where the nerve cells and synapses reside, that we so often discuss in mental health treatment. Brodmann’s Area • Korbinian Brodmann: Comparative Localization Studies in the Brain Cortex, its Fundamentals Represented on the Basis of its Cellular Architecture (1909): divided the neocortex into 52 regions based on: • Size • Number • Density of the cells • Local connections • Long tract projections to and from the subcortical regions • Made up of six layers, with few exceptions • Pyramidal neurons with their triangular-shaped cell bodies make up approximately 75% of the cortical neurons. • The local connections or interneurons are typically inhibitory Gamma- aminobutyric acid (GABA) neurons. Prefrontal Cortex • Front of the motor cortex. This is one of the anatomic structures that distinguishes humans from other mammals. • 29% of the cerebral cortex in humans (compared with 3.5% in the cat, 7% in the dog) • Dysfunction in the PFC is implicated as a possible source of pathology in many psychiatric disorder: depression, schizophrenia, anxiety, and attention deficit hyperactivity disorder (ADHD) • Four regions of the PFC: dorsolateral, ventromedial, orbitofrontal and the cingulate gyrus Hippocampus
• A folded structure incorporated within
the temporal lobe Essential in the development of memories • One of the few locations in the brain where stem cells reside • The volume of the hippocampus is decreased in various psychiatric disorders: post-traumatic stress disorder (PTSD) and major depression. Amygdala • Lies within the temporal lobe just anterior to the hippocampus • Divided into three regions: • the medial group, the central group, and the basolateral group. • The basolateral group, which is particularly large in humans, receives input from all the major sensory systems. • The central nucleus sends output to the hypothalamus and brain stem regions. • Links sensory input from cortical regions with hypothalamic and brain stem effectors (Amygdala is active when people are anxious and/or angry) Hypothalamus • Small cluster of nuclei makes • Controls basic functions as eating, drinking, sleeping, and temperature regulation • Receives input from four sources: the higher cortex, the brain stem, internal chemoreceptors, and hormonal feedback. • Has its own chemoreceptors that measure glucose, osmolarity, and temperature Hypothalamus • Receives feedback from the steroid hormones and neuropeptides • Divided into three zones: • Lateral zone - controls arousal and motivated behavior. • The medial zone - involved with homeostasis and reproduction. • The periventricular zone -includes the suprachiasmatic nucleus, cells that control the autonomic nervous system (ANS) and the neurosecretory neurons that extend into the pituitary Autonomic Nervous System • Two branches: • The sympathetic division: • Originates in the posterolateral region of the periventricular zone of the hypothalamus. • Controls the fight and flight response • Plays a prominent role in the physical symptoms of anxiety, for example, racing heart. • Send out their axons from the thoracic and lumbar regions to preganglionic neurons, which primarily reside in the sympathetic chain on either side of the spinal cord. • Cholinergic and adrenergic Autonomic Nervous System • The parasympathetic division: • Originates in the anterior cells of the same zone in the hypothalamus. • Mediate functions that the body performs in times of calm, forexample, digest food. • Emerge from the brain stem and sacral region of the spinal cord. • Exclusively cholinergic. • Complicates the treatment of mental disorders particularly when using the tricyclic antidepressants. (dry mouth, tachycardia, and constipation) Cerebellum • The cerebellum sits on top of the brain stem, at the back of the skull, below the cerebral cortex. • Involved with the coordination of movement, • Active in sensation, cognition, memory, and impulse control • Implicated to be playing a role in the pathophysiology of autism, ADHD, and schizophrenia. • Supportive structure for the cerebral cortex. Blood Brain Barrier • One of the mechanism the brain uses to maintain a controlled environment, isolated from the rest of the body. • Parts: Astrocytes foot processes, tight junctions and endothelial capillary cells • Few areas of the brain that have gaps in the BBB: The pituitary gland and some parts of the hypothalamus • Active transport mechanisms within the endothelial cell wall to bring these essential water-soluble substances into the brain. Neuronal Cells and Signaling Irene Carmelle S. Tan, MD, DSBPP Neuronal Cells • The cell body of the neuron is full of the usual assortment of organelles, although not in the same proportions as seen in non-neural cells. Neuronal Cells – Endoplasmic Reticulum • Endoplasmic reticulum and mitochondria are found more frequently in neurons than in other brain cells • Because of the increased need for protein synthesis and energy. Neuronal Cells – Ribosome • The ribosome is the organelle in which mRNA is translated into proteins. • attached to the endoplasmic reticulum (rough ER) or floating freely in the cytoplasm. • Once refined, are used by the cell for structural (e.g., receptors), functional (e.g., enzymes), or communication (e.g., neuropeptides) purposes Neuronal Cells – Golgi Apparatus • The Golgi apparatus is where much of the posttranslation refinement, sorting, and storage of proteins occurs • Enables proteins to be appropriately transported to distant sites within the cell such as the dendrites. Neuronal Cells – Mitochondria • The mitochondria are the energy generators of the neuron and are abundant in these cells • Reflects the active nature of the brain. • The mitochondria convert adenosine diphosphate (ADP) into adenosine triphosphate (ATP) • It is ATP that the cell uses to perform its functions. Neuronal Cells – Dendrites • The dendrites are the part of the neuron that sprout off the cell body and look like tree branches. • Receive input from other neurons and relay it to the cell body. • Dendritic spines - is the postsynaptic receptor for an incoming signal. • Dendritic abnormalities are the most consistent anatomic finding of mental retardation (reduction in the number and length of dendritic branches along with sparse and thin spines). Neuronal Cells – Axons • The axon is perhaps the most unique structure of the neuron. • Starting at the axon hillock and running either only a few micrometers or the length of the spinal cord • Transmit a signal quickly without degradation to other neurons or end organs. Neuronal Cells – Axons • Axoplasmic transport enables the neuron to send material down the microtubules to the distal ends of the cell. • The terminal end of the axon forms the synapse. Here the electrical signal sent down the axon is converted into a chemical signal, so that the neuron can communicate with its neighbor. • The neurotransmitters that form the basis of the chemical signal are stored in vesicles and diffuse across the synaptic cleft to the receptors on the postsynaptic dendrite when the vesicles open. Glial Cells • The glial cells that make up the rest of the cells in the central nervous system (CNS) actually outnumber the neurons by 9:1. • three kinds of glial cells: 1. The microglia are similar to macrophages found in the peripheral tissue. They respond to injury with a dramatic increase in their numbers and remove cellular debris from the damaged area. 2. The oligodendrocyte is considered the CNS equivalent of the Schwann cell in the peripheral nervous system. They are the cells that wrap myelin around the axons of the neurons and by acting as an electrical insulator greatly increase the speed of the transmission of the action potential. Complete myelinization of the prefrontal cortex is delayed until the second and even third decade of life. 3. The astrocyte is the star-shaped cell that fills the spaces between the neurons. It plays a role in maintaining the blood brain barrier, but other functions include regulating the chemistry of the extracellular fluid, providing structural support, and bringing nutrients to the neurons. It also plays in modulating the electrical activity at the synapse. Glial Cells Cell Sgnaling • All living cells maintain a negative internal electronic charge relative to the fluid outside of the cell’s roughly -60 mV in a neuron. • Nerve cells use the depolarization of this charge to signal other nerves or end organs. • The neuron first receives signals through the dendrites what are called postsynaptic potentials. • Second, the cell sums the incoming impulses and if high enough sends an impulse down the axon, an action potential. Cell Signaling • threshold and all-or-none - The neuron will sum up all the incoming post synaptic potential at the axon hillock. If the potential has depolarized to the threshold then an action potential is generated. • This occurs by the opening of the voltage-gated sodium channels and the rapid influx of positive ions. Voltage-gated sodium channel is a protein embedded in the lipid member of the cell. • The gated nature of the channel means that this type of pore allows a large and fast influx of the particular ions once the threshold has been crossed. Cell Signaling Cell Signaling • The arrival of the action potential at the terminal depolarizes the membrane, which opens the voltage-gated calcium channels. • The voltage-gated calcium channels are similar to the voltage-gated sodium channels except they are permeable to Ca2+. • Consequently, there is a large and rapid influx of Ca2+, which is required for exocytosis and the release of the neurotransmitter. Cell Signaling Neurotransmitters and Neuronal Tracts Irene Carmelle S. Tan, MD, DSBPP Neurotransmitters • Defined by meeting three criteria: 1. The substance must be stored in the presynaptic neuron. 2. It must be released with depolarization of the presynaptic neuron induced by the influx of Ca2+. 3. The substance must bind with a specific receptor on the postsynaptic neuron. • Neurotransmitters differ from hormones by their close physical proximity of the release to the receptor • Three basic categories: 1. The classic neurotransmitters 2. Neuropeptides 3. Unconventional neurotransmitters Classic Neurotransmitter: Amino Acids • Glutamate • It is the major workhorse of the brain • Makes up more than half of the excitatory neurons. • Do not cross the blood brain barrier. • Synthesized in the brain from glucose and other precursors. • Glial cells assist in the reuptake, degradation, and resupply of glutamate for neurons. Classic Neurotransmitter: Amino Acids • GABA and Glycine • GABA is the major inhibitory transmitter in the brain and is used by approximately 25% of the cortical neurons. • Glycine is the other inhibitory amino acid, but is less common. • GABA puts the brakes on the brain: not enough GABA and one can have seizures. • GABA interneuron quiets an overactive neuron. • Increasing GABAergic activity has been used to treat insomnia, pain, and anxiety, and to assist in the management of mania. Classic Neurotransmitter: Monoamine • Two principle classes of monoamines: • Catecholamines (DA, NE, and epinephrine) • Indoleamines (serotonin and melatonin) • All the monoamines are inactivated and degraded when taken back by the neuron. (Clinicians often refer to this as the reuptake pump, but neuroscientists call this the transporter, e.g., the DA transporter.) • The class of enzymes in the terminal that degrades the neurotransmitters is the monoamine oxidases (MAOs). • Consequently, MAO inhibitors cause an increase in catecholamines (e.g., DA, NE, and serotonin), by limiting the degradation process, with well- known benefits for depression and anxiety. Classic Neurotransmitter: Monoamine • Dopamine • DA neurons constitute approximately half a million of the cells in the brain • Substantia nigra located in the ventral midbrain has primary projections to the caudate and putamen (collectively called the striatum). • This pathway is called the nigrostriatal system or mesostriatal system. • As part of the basal ganglia this pathway is integral to voluntary movement. • Parkinson's disease is the result of a loss of DA neurons in the substantia nigra. • The extrapyramidal side effects due to antipsychotic medications can induce parkinsonian symptoms by blockade of these neurons. Classic Neurotransmitter: Monoamine • Dopamine • The cells of the ventral tegmental area, also in the ventral midbrain, project to the nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. • These innervations, called the mesolimbocortical DA system, are particularly dense in primates. • Subdivided to 2 branches: • mesolimbic (nucleus accumbens, amygdala, and hippocampus) • mesocortical (prefrontal cortex) Classic Neurotransmitter: Monoamine • Dopamine • The short tracts in the arcuate nucleus of the hypothalamus called the tuberoinfundibular DA system release DA into the portal veins of the pituitary gland. • The synthesis and release of prolactin in the anterior pituitary is inhibited by this DA. • Any process that interrupts the action of DA on the prolactin-producing cells will lead to hyperprolactinemia. • Antipsychotic medications that block the DA receptor can cause an increase in prolactin Classic Neurotransmitter: Monoamine • Dopamine • In summary there are 4 tracts: 1. Nigrostriatal tract – controls movement (parkinsonian symptoms) 2. Mesolimbic tract – projects to the limbic system (positive symptoms in schizophrenia) 3. Mesocortical tract – projects to the prefrontal area (negative symptoms in schizophrenia) 4. Tuberoinfundibular tract – controls prolactin (hyperprolactinemia with the use of antipsychotic) Classic Neurotransmitter: Monoamine • Norepinephrine • Noradrenergic neurons - contain an additional enzyme in their terminals that converts DA to NE. • Approximately 50% of the NE neurons are located in the locus coeruleus. • Project to virtually every area of the brain and spinal cord. • Noradrenergic neurons are important in handling danger (Sympathetic nervous system) • NE is cleared from the synaptic cleft by a reuptake transporter that is also capable of taking up DA. Classic Neurotransmitter: Indoleamines • Serotonin (5-hydroxytryptamine) • Synthesized from tryptophan that must be obtained in the diet (grains, meats, and dairy products are good sources of tryptophan). • Levels of serotonin in the brain can be lowered significantly with insufficient dietary tryptophan. • In the pineal gland there are two additional enzymes that convert serotonin to melatonin, the other indoleamine. • Cell bodies are relatively few and reside in the raphe nuclei in the brain stem. • As with NE, the serotonin neurons project to virtually all areas of the brain. Classic Neurotransmitter: Indoleamines • Histamine • Released from mast cells as part of an allergic reaction in the peripheral tissue • In the brain, it is involved in arousal and attention. • Most of the cell bodies start in the tuberomammilary nucleus of the posterior hypothalamus • When animals are alert, the histamine neurons are active. • Histamine neurons are quiet when animals are sleeping. Classic Neurotransmitter: Indoleamines • Acetylcholine • Only small molecule transmitter that is not an amino acid or directly derived from one. • Not a monoamine, but is often grouped with these neurotransmitters due to similar size and distribution. • Plays a prominent role in the peripheral ANS and is the neurotransmitter at the neuromuscular junction. • Projections to the hippocampus that are involved with learning and memory and are disrupted in Alzheimer's disease. Neuropeptides • The neuropeptides are small chains of amino acids, which are considerably larger than the classic neurotransmitters. • Initially, the peptide is a large propeptide precursor, which is cleaved into an active neuropeptide as it is moved from the Golgi apparatus • Not recycled by the neuron, but are rather broken down by degradative enzymes (peptidases) on the receptor membrane. • Examples: • adrenocorticotropic hormone (ACTH), luteinizing hormone, somatostatin, and vasopressin • endorphins and enkephalins Unconventional Neurotransmitters • Gas: Nitric Oxide • Most commonly associated with erectile dysfunction, • Formed in glutamate neurons when arginine is converted into citrulline and NO. • Diffuse (without obstruction) out of the originating cell, through the extracellular medium and into any neighboring cell that it meets. • Converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (GMP) that acts as a second messenger. • Send a message to the neighboring cells that signals an increase in activity Unconventional Neurotransmitters • Endocannabinoids • Main active compound of marijuana is tetrahydrocannabinol (THC), which binds to the cannabinoid receptor and causes the well-known euphoria, calm, distorted cognition, and munchies • The cannabinoid receptor 1 (CB1) is widely expressed throughout the brain on presynaptic terminals. • calming effect of marijuana. • activating or blocking the CB 1 receptor for therapeutic reasons such as pain, anxiety, and nausea are being pursued vigorously. • Potential for a weight loss treatment • Rimonabant - selective blocker (antagonist) of the CB1 receptor - facilitate weight loss • The cannabinoid receptor 2 (CB2) implicated in depressing the immune system Receptors and Signaling of the Nucleus Irene Carmelle S. Tan, MD, DSBPP Fast Receptors: Chemical • Ion channel (also called transmitter-gated ion channel). • A neurotransmitter or medication stimulates the opening of the pore inside the receptor and ions rapidly flow into the cell. • Positive ions (Na+ or Ca2+ ) • Result in an excitatory postsynaptic potential (EPSP) • Acetylcholine and glutamate • Negative ions (Cl-) • Result in inhibitory postsynaptic potentials (IPSPs) • Gamma-Aminobutyric acid (GABA) and glycine Amino Acid Receptors • Mediate most of the fast transmitter-gated channels in the brain. • The receptors, unlike the transmitter, come in a variety of style a relationship that is much like feet and shoes. • ”You only have two feet, but many shoes.” • Categorized as: • different classes • different subtypes within a class • Examples: Glutamate and GABA receptors Glutamate • Three prominent glutamate receptors: N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate • NMDA and AMPA receptors, which often coexist on the same postsynaptic receptor, both allow the rapid entry of Na+ into the cell that generates the depolarization • NMDA receptors are unique in that they also allow the entry of Ca2+ that can act as a second messenger inside the cell. Glutamate • The NMDA receptor is further unique in that it requires both the glutamate transmitter and a change in the voltage to open before it will allow the entry of Na+ and Ca2+. • This property is due to the presence of Mg2+ ions, which clog the NMDA receptor at resting voltage. Gamma-Aminobutyric Acid • GABA and glycine are the primary inhibitory neurons in the brain • Too much inhibition causes the brain to slow down even lose consciousness • Too little inhibition can result in seizures. • GABA receptor has several other sites where chemicals can modulate its function. These include ethanol, barbiturates and benzodiazepine. • Steroid hormones can also modulate GABA receptors which may explain the psychiatric symptoms that develop at times of drop in sex hormone levels Slow Receptors: Metabolic • G-protein coupled receptor • Basic style involves three steps: • A neurotransmitter binds to the receptor. • The receptor activates the G-protein, which moves along the intracellular membrane. • The G-protein activates the effector protein. • Trigger a process called the secondary messenger cascade • Examples: cAMP and Adenyl Cyclase • Examples of Metabolic receptors: serotonin, dopamine, norepinephrine and histamine receptors Serotonin Receptors • The 5-HT1 receptors make up the largest subtype with 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. • 5-HT1A play a prominent role in depression and anxiety. It is an autoreceptor on the cell body. Stimulation of this receptor reduces cell firing and curtails the release of serotonin. • Buspirone (Buspar) is a partial 5-HT1A agonist, which suggests that 5- HT1A has some role in anxiety. Serotonin Receptors • The 5-HT1D receptor is also an autoreceptor but is located on the nerve terminal at the synapse. The 5-HT1D receptor is stimulated by the antimigraine drug sumatriptan (Imitrex). • The 5-HT2A plays an important role in the “atypicalness” of the second-generation antipsychotic agents (clozapine, risperidone, olanzapine, etc.). • Blockade of 5-HT2A decrease in extrapyramidal symptom (EPS) and greater cognitive improvements. Serotonin Receptors • In summary, • 5-HT1A stimulation – anti-depressant and anti-anxiety. • 5-HT1D receptor stimulation – anti-migraine • 5-HT2A antagonism - decrease in extrapyramidal symptom (EPS) and greater cognitive improvements in patients taking atypical antipsychotics Dopamine Receptors • The dopamine receptors are involved in a wide range of functions including locomotion, cognition, psychosis, and even neuroendocrine secretion. • Increased D2 receptor antagonism correlates with the therapeutic efficacy and EPS side effect with the traditional antipsychotics. • There is great interest in the D2-like receptors (D3 and D4) as possible alternative sites for antipsychotic agents • The psychostimulants (cocaine, amphetamine, methylphenidate, etc.) work in part by blocking the reuptake of dopamine and leaving more dopamine in the synapse to stimulate the dopamine receptors. • Augmenting D1 and D2 receptors (agonists) are the mainstay of treatment for Parkinson's disease. Dopamine Receptors • In summary, • Increased D1 and D2 agonism - treatment for Parkinson's disease • Increased D2 antagonism - EPS and antipsychotics effects • D3 and D4 - possible alternative sites for antipsychotic agents • All Dopamine receptors – site of action of psychostimulants (cocaine, amphetamine, methylphenidate, etc.) Adrenergic Receptors • alpha1 receptor • play a role in smooth muscle contraction and has been implicated in effecting blood pressure, nasal congestion, and prostate function. • Stimulation may synergistically increase the activity of the serotonin neurons in the raphe nucleus • alpha2 receptor • subtypes in the CNS inhibit the firing of the norepinephrine neurons. • mediate the sedative and hypotensive effects of clonidine. • decreases sympathetic activity(slows cardiac rhythm and lowers blood pressure) Histamine Receptors • The H1 receptor • Agonism of H1 receptor may lead to arousal • Antagonism of H1 receptor may lead to weight gain and sedation • The H2 receptor • Antagonism of H2 - used treatment for peptic ulcer disease. • The H3 receptor • not clearly understood, but may be involved in appetite, arousal, and cognition. Cholinergic Receptors • Nicotinic receptor • Cholinergic receptors in skeletal muscle • Muscarinic receptor • Cholinergic receptors in the heart • ACh is important in cognition and memory • Inhibiting acetylcholinesterase is a treatment for Alzheimer's disease. Signaling the Nucleus Long-Term Potentiation • Once a neuron has been exposed to high-frequency stimulation, something changes, and now a single stimulus will generate a high EPSP. • LTP demonstrates that neurons can incorporate lasting changes, which is an essential step to developing memories and skills. • Both glutamate receptors (NMDA and AMPA) must be operational for the process to work • Strengthening of connection between two cells due to more transmitters and more receptors resulting in a stronger signal. • Development of new spines on the postsynaptic dendrite in the hippocampus is a manifestation of learning and memory. Genetics and Epigenetics Irene Carmelle S. Tan, MD, DSBPP Genetics • Genetics is the DNA code for what a cell can transcribe into specific types of RNA or translate into specific proteins. • there are over 20 000 genes in the human genome, it does not mean that every gene is expressed, even in the brain. Epigenetics • Epigenetics is a parallel system that determines whether any given gene is actually made into its specific RNA and protein, or if it is instead ignored or silenced. • If the genome is a lexicon of all protein “words,” then the epigenome is a “story” resulting from arranging the “words” into a coherent tale. Molecular Mechanisms of Epigenetics • In addition, malfunctioning neurons are impacted by inherited genes that have abnormal nucleotide sequences, which if expressed contribute to mental disorders. • Thus, the story of the brain depends not only on which genes are inherited but also on whether any abnormal genes are expressed or even whether normal genes are expressed when they should be silent or silenced when they should be expressed. • Neurotransmission, genes themselves, drugs, and the environment all regulate which genes are expressed or silenced, and thus all affect the story of the brain Molecular Mechanisms of Epigenetics • Epigenetic mechanisms turn genes on and off by modifying the structure of chromatin in the cell nucleus • The character of a cell is fundamentally determined by its chromatin, a substance composed of Nucleosomes. • Nucleosomes are an octet of proteins called histones around which DNA is wrapped • Chemical modifications that can do this include not only methylation, but also acetylation, phosphorylation, and other processes that are regulated by neurotransmission, drugs, and the environment Thank you!