Neurotransmitters and Brain Metabolism

• Blood-brain, blood-CSF, and meningeal barriers are the three types of brain barriers.

Blood-Brain Barrier (BBB)

• The blood-brain barrier (BBB) exists between the lumen of cerebral blood vessels and the brain parenchyma.
• The BBB is collectively known as the blood brain barrier.
• BBB capillaries in the brain resemble non-fenestrated capillaries in muscle,
• There are tight junctions between the endothelial cells that limit the passage of substances through the junctions.
• The endothelium contains relatively few vesicles and exhibit little vesicular transport.
• A basement membrane surrounds the pericytes outside the endothelial cell.
• Astrocytic end-feet surround these structures from nearby astrocytes and adhere to the capillaries' basal lamina, leaving gaps of about 20 nm.
• These mentioned structures are often referred to as the neurovascular unit.

Blood-CSF Barrier

• The choroid plexus plays a crucial role in producing cerebrospinal fluid (CSF).
• It is located at lateral ventricles, the 3rd and 4th ventricles.
• Between choroid plexus and CSF, there is a blood-CSF barrier.
• Unlike ependyma, the lining epithelial layer has tight junctions on the side facing the ventricle (apical surface).
• Gaps exist between the endothelial cells of the capillary wall, blood vessels are fenestrated, and form a nonrestrictive barrier.

Meningeal Barrier

• The meningeal barrier is the least studied and structurally most complex of the brain barriers.

Circumventricular Organs

• These are regions of the brain that are not covered by the BBB
• Sometimes our brain needs to sense chemicals and gases in our blood directly
• Sometimes our brain needs to send hormones directly into the blood
• These parts are found around the ventricles

Sensory and Secretory Organs

• Circumventricular organs are areas outside the BBB that are near the brain stem and have fenestrated capillaries.
• Circumventricular organs can be classified as sensory or secretory
• Sensory organs can sense plasma molecules
• They provide information to the autonomic nervous system from the systemic circulation
• Sensory organs include:
  • Area postrema
  • Subfornical organ (SFO)
  • Vascular organ of the lamina terminalis
• Secretory organs are responsible for secreting hormones and glycoproteins.
• Secretory organs include:
  • Subcommissural organ.
  • Posterior pituitary.
  • Median eminence.
  • Pineal gland.

Blood-Brain Barrier Functions

• This maintains a constant environment for neurons in the CNS.
• It also shields the brain from endogenous or exogenous toxins.
• It prevents neurotransmitters from escaping functional sites in the CNS into general circulation.
• Drug penetration varies depending on the drug: non-ionized (lipid-soluble) drugs being able to cross the barrier more readily than ionized (water-soluble) drugs.
• Inflammation, irradiation, and tumors may compromise the blood-brain barrier and permit substances that are usually excluded, such as antibiotics and radiolabeled markers, to enter the brain.
• The blood-brain barrier is immature at birth.
• Lipid-soluble free forms of steroid hormones, water, CO2, and O2 penetrate the BBB easily.
• Protein-bound forms, proteins, and polypeptides generally do not penetrate the BBB

Cerebral Blood Flow Regulation

• Cerebral blood flow is closely related to tissue metabolism and is highly restricted.
• Several metabolic factors are believed to contribute to cerebral blood flow regulation.
• Carbon dioxide is the most important cerebral vasodilator, but it increases hydrogen ions that induce dilation.
• Small arterial CO2 changes can impact cerebral blood flow; a 1 mmHg variation changes blood flow by 3-4%.
• Low oxygen leads to vasodilation to increase flow
• The rate of oxygen utilization by the brain is 3.5 (±0.2) milliliters of oxygen per 100 grams of brain tissue per minute.
• Cerebral tissue oxygen partial pressure usually ranges from 35 to 40 mm Hg.
• Oxygen deficiency (below 30mm Hg) almost immediately causes vasodilation, and a cerebral PO2 fall below 20 mmHg can lead to a coma.

Substances Released from Astrocytes

• Gray matter astrocytes (protoplasmic astrocytes) extend fine processes that cover most synapses.
• Neurotransmitters released from active neurons join the metabotropic glutamate receptor at astrocytes.
• This increases calcium inside astrocytes
• Vasodilator mediators like nitric oxide, arachidonic acid metabolites, potassium ions, and adenosine are released from astrocyte end-feet onto blood vessels.
• Astrocytes have processes called end-feet and cover synapses

Arterial Blood Pressure

• Cerebral blood flow is autoregulated well between arterial pressure limits of 60 and 140 mm Hg and the flow is constant
• Cerebral blood flow is autoregulated well between arterial pressure.
• Arterial pressure can change during daily activities but cerebral flow remains constant.

Intracranial Pressure

• It is the pressure inside the skull, including that in the brain tissue and CSF.
• It is also the pressure applied on the brain by blood, mass, or CSF.
• Normal intracranial pressure is less than 15 mmHg while in a supine position.
• The cranial cavity has contains a brain weighing around 1400 g and 75 mL each of blood and spinal fluid.
• Tissue and fluid like the brain and spinal have incompressible properties, so volume is constant and pressure is related to volume (Monro-Kellie doctrine).
• Intracranial pressure can increase by mass, brain swelling, higher venous pressure, obstructed CSF flow, or higher CSF production.
• High intracranial pressure can cause collapsed veins, less efficient cerebral perfusion pressure, and cut cerebral blood flow.

Cerebral Perfusion Pressure

• Mean Arterial Pressure (MAP) pushes cerebral blood in
• Mean Venous Pressure (MVP) Pushes cerebral blood out
• Cerebral Perfusion Pressure(CPP) = MAP - MVP
• The rise in venous pressure decreases cerebral blood flow.
• The cerebral vessels are compressed whenever the intracranial pressure rises.

Nerves Innervating Cerebral Blood Vessels

• Postganglionic sympathetic neurons: Cell bodies are in the superior cervical ganglia, containing norepinephrine and neuropeptide Y. and stimulate vasoconstriction.
  • Sympathetic stimulation of vasoconstrictor effect will be countered by "auto-regulation"
• Postganglionic cholinergic neurons: These originate in the spheno-palatine ganglia also innervate vessels, and contain acetylcholine.
• Sensory nerves: Found more in distal arteries, their cell bodies are in the trigeminal ganglia, and contain substance P, neurokinin A, and calcitonin gene-related peptide (CGRP). touching.
• Pulling on vessels causes headaches.

Cerebral Microcirculation

• Cerebral blood vessels increase with area having high metabolic rate ( gray matter more than white matter); blood flow in each segment of the brain changes from 100 to 150% in seconds
• Cerebral blood vessels less leaky than other body parts (BBB) because BBB exists
• No true lymphatics are present in the brain, excess protein in the brain tissue leaves the tissue flowing with fluid through the perivascular spaces into the subarachnoid spaces.

Brain Metabolism

• Under resting but awake conditions, the metabolism of the brain accounts for about 15 percent of the total metabolism in the body.
• The major need for metabolism in the neurons (70%) is for Na-K ATPase
• Brain cells are supplied primarily by dependent by glucose in the blood, and are insulin-independent for the ability to uptake said glucose.
• Brain cells lack significant anaerobic metabolism, and so are sensitive to time without oxygen or glucose, surviving 2 minutes
• GLUT is a type of glucose transporter that carries many cell types, and the brain uses them rather than insulin dependent cells/transporters
• One major function of the cerebrospinal fluid is to cushion the brain within its solid vault
• The brain weighs about 1400 g in air, but in the CSF "water bath," its net weight is only 50g.
• Removing CSF during lumbar puncture can cause a severe headache because the brain hangs on the vessels and nerve roots, and traction on them stimulates pain fibers.

CSF: Plasma Composition Comparison

• Higher levels: Na+, Cl−, Mg2+, and creatinine.
• Lower levels: K+, Ca2+, protein, glucose, amino acids, lactate, and cholesterol.

CSF

• CSF fills the ventricles, in humans, it is about 150 mL and the rate of CSF production is about 550 mL/d.
• CSF turns over about 3.7 times a day.
• 50-70% of the CSF is formed in the choroid plexuses while the remainder is formed around vessels
• Hydrocephalus is a medical condition, caused by the skull having openings that are too small to allow fluids to pass properly

Explore neurotransmitters, brain metabolism, and intracranial pressure. Learn about grey matter, blood flow regulation, and glucose transport within the brain. Understand the effects of increased intracranial pressure and the function of norepinephrine.