Neurobiology Exam 2

Anatomy of neuron

cell body, axon, dendrites

-Function in circuits

cell body

generates electrical signals in the form of action potentials

axon

carry the electrical signals generated by the cell’s body to allow communication between neurons ends at synaptic terminals

dendrites

branching, allowing several neurons to communicate with one another at locations called synapses

Neuroglial cell types

central nervous system: astrocytes, ependymal, oligodendrocytes, microglia

Peripheral nervous system: satellite cells, schwann cells

astrocytes

Maintain blood brain barrier

-controlling the levels of neurotransmitters around synapses

-regulating ions, and providing metabolic support

ependymal cells

Line the spinal cord and ventricles of the brain

-involved in producing cerebrospinal fluid (CSF)

oligodendrocytes

myelinate CNS axons

-provide a structural framework

microglia

The brain’s immune cells

-remove dead cells and pathogens by phagocytosis

satelliite cells

surround neuron cell bodies in ganglia

-regulate neurotransmitter levels

schwann cells

myelinate neurons in the PNS

-maintenance and regeneration of neurons after injury

Gliial cells do what in the development of the nervous system in the physiological function?

-maintaining solute and nutrient homeostasis

-assisting neurons in reaching their target locations

-creating cellular boundaries

critical period (CP)

Circuits are refined in an activity-dependent manner during a short time period of heightened plasticity

-involves extensive pruning of the axons and dendrites to achieve their correct and final structures.

classes of known growth inhibitors 

Myelin-associated inhibitors and chondroitin sulphate proteoglycans

Myelin-associated inhibitors

proteins expressed by oligodendrocytes that stabilize myelin sheaths but also inhibit axon growth

-example: Nogo-A, myelin-associated glycoprotein (MAG), semaphorin

Chondroitin sulphate proteoglycans (CSPGs)

Secreted by astrocytes play an active role in neural development, inhibiting axon growth to create borders in the nervous system

Spinal cord injury (SCI)

damage to the spinal cord that temporarily or permanently causes changes in its function

Traumatic SCI

occurs when an external physical impact (motor vehicle injury) acutely damages the spinal cord

primary injury

The initial traumatic event that caused mechanical disruption and dislocation of the vertebral column, which causes compression or transection of the spinal cord

-damages neurons and supporting cells, compromising the blood-brain barrier

secondary injury

happens after the primary injury and is characterized by an acute phase (0-48 hours after injury)

-oedema, haemorrhage, ischaemia, inflammatory cell infiltration, the release of cytotoxic products, and cell death

-leads to necrosis and/or apoptosis of neurons and glial cells, such as oligodendrocytes, which can lead to demyelination and the loss of neural circuits

What happens after secondary injury?

The spinal cord lesion evolves to chronic phases (attempts at demyelination, vascular reorganization, alterations in the composition of the extracellular matrix (ECM), and remodeling of neural circuits 

cystic cavitations

The overwhelming cell death and degeneration in the acute phase of injury promote loss of tissue volume and formation of cystic cavities

-formidable barrier to directed axonal regrowth and is a poor substrate for cell migration 

glial scar

a zone around the cystic cavities appears, in which reactive astrocytes proliferate and tightly interweave their processes, creating a mesh-like array

-restricts axon regeneration and anatomical plasticity by inhibiting neurite outgrowth

Why can’t CNS axons regrow?

• Chondroitin sulphate proteoglycans: actively inhibit axon regrowth and regeneration after injury

  • They get secreted by astrocytes in glial scars and are both membrane-bound and secreted into the extracellular space

• Myelin-associated inhibitors: after injury, remain at the site with myelin debris, impairing neurite outgrowth

What can SCI affect in the sympathetic nervous system?

-Preganglionic sympathetic neurons originate in the spinal cord

-spinal shock, neurogenic shock

spinal shock

altered physiologic state immediately after a spinal cord injury, which presents as loss of spinal cord function caudal to the level of the injury, with flaccid paralysis, absent bowel and bladder control, and loss of reflex activity

neurogenic shock

a combination of both primary and secondary injuries that lead to loss of sympathetic tone and thus an unopposed parasympathetic response driven by the vagus nerve. Consequently, patients suffer from instability in blood pressure, heart rate, and temperature regulation

What to use to diagnose SCI?

sensory tests, motor tests, reflex tests

-timing and medical history

sensory test

including the feelings of hot, cold, touch, pain, pressure, and body position

motor test

for movement of different limbs, neck

tetraplegia

It is a paralysis caused by an injury to the cervical spinal cord. Affecting all limbs

Paraplegia

Paralysis caused by an injury to the lower thoracic and lumbar spinal cord. Affects lower limbs and some parts of forelimbs

short-term treatment for SCI

haemodynamics, decompressive surgeries

haemodynamics

maintaining adequate spinal cord perfusion

decompressive surgeries

realign spinal cord and decompress it

chronic/long term treatment of SCI

physical rehabilitation, functional electrical stimulation

physical rehabilitation

focused on regaining function, enhancing any remaining function and preventing complications

-strength training, cardiovascular-focused exercise, respiratory conditioning transfer, mobility training and stretching to prevent muscle contractures (permanent shortening of muscle)

functional electrical stimulation

use small pulses of current to activate muscles and has been successfullyused in the upper extremities for eating, gripping and writing

-can be surgically implanted with electrodes on the anterior sacral nerve roots to provide patients with controllable bowel or bladder function

what happens to the CNS when it is damaged?

-axons do not regenerate

-can result in permanent loss of function

what happens to peripheral nerves when damaged?

-nerves can regenerate after injury

-sensory nerve damage, motor nerve damage, autonomic nerve damage

what neuroglia cell type helps the CNS?

oligodendrocytes

oligodendrocytes

-Invest large axons in myelin, and astrocytes regulate ion and metabolite concentrations in the neuropil, combined responsibility of Schwann cells in the PNS.

-secrete no basal lamina

wallerian degeneration 

The peripheral nerve initiates a complex series of several cellular and molecular changes

peripheral nerve injury and regeneration

-Wallerian degeneration

-Schwann cells recruit macrophages to scavenge degenerative myelin fragments

-meanwhile SCs proliferate and migrate along the basal lamina, which guides axons to reinnervate towards the corresponding target

How does PNS overcome SCI?

-CSPGs that inhibit axon regrowth are not produced by Schwann cells

-Myelin debris is cleared effectively within 2 to 3 weeks of injury (CNS myelin debris can still be found littering degenerated tracts months to even years after injury)

-Schwann cells secrete a basal lamina composed of growth-promoting laminin, type IV collagen, and heparin sulfate proteoglycans (HSPGs), which is crucial to the ability of these cells to myelinate

difference between humans and zebrafish

-A complex glial scar is formed by invading immune cells and reactive oligodendrocytes and astrocytes, which constitutes a hostile environment to axon growth 

-Reactive cells promote axonal regrowth (bridging) across the lesion site (zebra fish)

Clinical trials as a treatment for SCI (cellular transplantation)

Cellular transplantation: of various cell types to repair the injured spinal cord, addresses the extensive loss of tissue caused by SCI that cannot be replaced by endogenous repair processes

-transplanted cells can replace lost cells, modulate the injury environment, and stimulate synergistic regenerative programs

clinical trials as a treatment for SCI (neurogenerative treatments)

-Nogo-A: found in the CNS and has a role in preventing the formation of new functional connections post-SCI

-Nogo-A antibodies: shown promise in promoting axonal regeneration in preclinical SCI studies

clinical trials as a treatment for SCI (neuroprotective treatments)

riluzole

Riluzole

a sodium channel blocker, improved neurobehavioural and pathological outcomes in animal models of SCI and is thought to prevent continuous activation of neuronal voltage-gated sodium channels, preventing cellular swelling and death, reducing excitotoxicity

clinical trials as a treatment for SCI (use of robotics)

First robotic exoskeleton (Re-walk, Re-Walk Robotics) with paraplegia, which fits around the legs and back of patients to facilitate sitting, standing, and walking

-hopes for use in conjunction with the discussed biological treatments to help optimize outcomes in the long term

traumatic layers of brain injury

scalp, skull, blood vessels, brain

pathophysiology similar to traumatic SCI

-blood-brain barrier dysfunction caused by TBI insult allows migration of activated leukocytes into the injured brain neuronal tissue

-activated leukocytes, microglia, and astrocytes produce ROS and inflammatory molecules such as cytokines and chemokines that contribute to demyelination and disruption of the axonal cytoskeleton, leading to axonal swelling and accumulation of myelin debris

-progressive axonal damage results in neurodegeneration

glial scar formation

-caused by astrogliosis at the lesion site, which creates a non-permissive environment that impedes axonal regeneration

-excessive accumulation of glutamate neurotransmitter leads to excitotoxicity and more cell death

symptoms of TBI

frontal: lack of focus, irritability, language difficulty

parietal: difficulty woth reading, spatial misperception

occipital: blind spots, blurred vision

temporal: problems with short- and long-term memory

cerebellum: difficulty walking, slurred speech

brainstem: changes in breath, difficulty swallowing

TBI treatment map

emergency evaluation, emergency department, intensive care unit, specialty neurotrauma polytrauma (comprehensive integrated inpatient brain injury rehabilitation hospita/skilled nursing facility), and long-term care (independent living, supported living program group homes, supported living program apartment, home with family and home services, nursing care facility

What are infections?

The invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the
infectious agent and the toxins they produce.

-can be caused by a wide range of pathogens

-multiple sites for pathogen entry

What is the normal body reaction to infection?

The immune system is a complex network of organs, cells
and proteins that defend the body against infection, whilst
protecting the body's own cells.

what parts of the body s considered part of the immune system?

-mucous membranes, tonsils, lymphatic vessels

-thymus, lymph nodes, skin, spleen, bone marrow

Fever or Pyrexia

the elevation of an individual's core body temperature above a 'set-
point' regulated by the body's thermoregulatory
center in the hypothalamus

cytokines

-Infections or other conditions like malignancy and autoimmune
reactions cause the release of immunological mediators

-trigger the thermoregulatory center of the hypothalamus, leading to an increase in the body's core
temperature

What do white blood cells do in the body?

an important and necessary part of your immune system. Produced in your bone marrow, they
defend your body against infections and disease

leukocytosis

high WBC

why is it rare for pathogens to infiltrate the CNS?

There are three biological barriers established by different cells at three key interfaces: the blood–blood-brain barrier (BBB), the blood–CSF barrier (BCB), and the arachnoid barrier

blood-brain barrier (BBB)

-formed by microvascular endothelial cells lining the cerebral capillaries penetrating the brain and
spinal cord of most mammals and other organisms with a well-developed CNS

-playing a critical role in protecting the neurons from blood-borne agents and providing a significant
obstacle to the entry exogenous compounds (including drugs) into the central nervous system

endothelial cells

epithelial cells that form the walls of blood
vessels. CNS ECs have unique properties compared with ECs in other tissues that allow them to tightly regulate the movement of ions, molecules, and cells between the blood and the brain.

Basement membranes (basal lamina)

-surrounds the vascular tube

-are extracellular matrix that provide an anchor for
many signaling processes, and provides an additional barrier for molecules and cells to cross before accessing the neural tissue

pericytes (PC)

-cells that sit on the outer surface of the endothelial
tube and are embedded in the vascular Basement Membrane. CNS capillaries have the highest PC coverage of any tissue

-play important roles in deposition of extracellular matrix, wound healing, regulating immune cell infiltration, and regulation of blood flow in response to neural activity

astrocytes

-provide a cellular link between the neurons and blood vessels (not part of the BBB)

-This helps neurons never be in direct contact with the blood, making it harder for blood-borne pathogens to reach neurons

cerebrospinal fluid barrier (BCB)

a specialized structure that separates the blood in
the brain's capillaries are from the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord

choroid plexus

secretes CSF

what difference is between BBB and BCB?

-BBB is sealed by tight junctions and does not show any permanent fenestration

-BCB has several fenestrations (gaps) which form a macro filter for proteins, but make it more vulnerable to microbial attack.

arachnoid barrier

-The third barrier is in the meninges, protective membranes that cover and support the brain and spinal cord. Blood vessels in the dura mater do not directly contact CSF or neurons.

-forms tight junctions to separate blood from the inner structures of the brain.

-aka avascular arachnoid epithelium, underlying the dura mater

-formed by arachnoid fibroblast-like cells joined by tight junctions, which separate blood within fenestrated dural capillaries from subarachnoid CSF

How do CNS infections happen?

The BBB and BCB are effective in protecting the CNS, but as with many barriers, they are not perfect. There are 3
ways by which a microbe can enter the CNS

transcellular CNS penetration

-Microbes cross through endothelial cells. They gain
access to the luminal side of the blood vessel endothelium, where they traverse through the
endothelial cells themselves.
-Once they’ve crossed the barrier, these microbes exit through the other side of the cell that’s in
direct contact with astrocytes, microglia, and neurons.
-Eg: E coli

paracellular CNS penetration

-Microorganisms attach to the Basement Membrane and enters the CNS between two endothelial cells. Tight junctions, the anchors that hold adjacent endothelial
cells close together, are disrupted during this mechanism of microbial transfer.
E.g. T pallidum

infected phagocytes

-the direct movement of a microorganism across the BBB in trans- and paracellular microbial transfer, the
Trojan-Horse method is an indirect form of microbial transfer.
-The BBB is permeable to phagocytic white blood cells, which regularly circulate in the
blood to provide immunological surveillance, migrating in and out of
tissues. Some microorganisms co-opt this natural process and use it to their
advantage. In the Trojan-Horse method, microbial transfer occurs with the
transmigration of an infected phagocyte. As an infected white blood cell crosses the
BBB, the microorganism also gains access to the CNS.
Eg: HIV

encephalitis

-Inflammation of the active tissues of the brain caused by an infection or an autoimmune
response. The inflammation causes the brain to swell, which can lead to headache, stiff neck, sensitivity to light, mental confusion, and seizures

-mild flu-like symptoms 

-Problems with speech or hearing
Double vision
Hallucinations
Personality changes
Loss of consciousness
Loss of sensation in some parts of the body
Muscle weakness
Partial paralysis in the arms and legs
Impaired judgment
Seizures
Memory loss
Prosopagnosia

myelitis

inflammation of the spinal cord

prosopagnosia

inability to recognize faces

meningitis

The inflammation of the meninges, tissues surrounding the brain

-Results in headaches and nausea

abscess

-a focal infectious mass lesion within the brain parenchyma that has central necrosis,
inflammatory neutrophilic infiltration, and capsule formation

-generally a secondary infection from extracerebral primary sources that spread to CNS either through the
blood or contiguous spread from adjacent structures.

-Usually bacterial infections cause this

-fever, loss of appetite, headache, and vomiting. Other symptoms that can occur
are neck pain, stroke, fits, or coma

diagnosis

medical history, physical examination, laboratory screening, analysis of the cerebrospinal fluid, conclusive tests

conclusive tests

MRI, Lumbar puncture (spinal tap)

lumbar puncture (spinal tap)

a medical procedure in which a needle is inserted into the
spinal canal, most commonly to collect cerebrospinal fluid
for diagnostic testing.

multiplex PCR

-a technique in which multiple primers are used, allowing detection of several organisms by a
single assay

-Bacterial infections are more acute than viral infections. Symptoms are more rapid onset for bacterial infections than viruses
-Blood protein levels are higher in bacterial infections than in
viral infections

-Blood glucose levels are lower in bacterial infections than in viral infections because of Septic shock. Sepsis occurs when chemicals released in the bloodstream to fight an
infection trigger inflammation throughout the body. It is fatal

how to survive encephalitis

-early detection and effective treatment of the underlying cause.
-Treatments depend on the pathogen causing the infection:
•Antiviral medications to fight viral infections affecting the brain.
•Antibiotics to address underlying bacterial infections

-Infections of the CNS will affect the whole body, patients might require a stay in the ICU so that
health care providers can watch for seizures, brain swelling, respiratory failure or heart rhythm changes.
•Symptomatic treatments might be given to control seizures
•A breathing tube, urinary catheter, or feeding tube may be necessary if the person’s encephalitis has caused loss of consciousness/voluntary/involuntary motor control

how to prevent CNS infections

vaccines, sanitation and hygiene

vaccine

an attenuated version of a biological preparation (usually a virus) that
provides active acquired immunity to a particular infectious disease

conditions that mimic CNS infections (especially encephalitis)

autoimmune encephalitis, tumors, metabolic encephalopathy

autoimmune encephalitis

progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic proteins progressive inflammation of the brain associated with antibodies against neuronal cell surface and
synaptic proteins

metabolic encephalopathy

caused by a chemical imbalance in the blood.
The imbalance is caused by an illness or organs that are not working as well as they
should

What makes a neuron special?

electrical excitability: multiple ion channels that allow ions through (current)

Chemical transmission of the current signal to the next cell through a specialized structure- synapse

depolarization

when the membrane potential is more positive than resting, caused by opening of voltage gated Na+ channels allowing Na+ ions to rush into the neuron

repolarization

caused by opening of voltage gated K+ channels allowing K+ ions to rush back out of the cell. Na+ channels are inactivated at this voltage

hyper polarization

when the membrane potential is more negative than resting

what makes neurons excitatory?

glutamate/acetyl choline

-principal cells

-glutamate synapse

-depolarizing

-promote firing

what makes neurons inhibitory?

GABA/ glycine

-interneurons

-GABA synapse

-hyperpolarizing

-suppress firing

feedback inhibitory network layer 5 cortex

Excitatory pyramidal neurons excite other pyramidal neurons and inhibitory interneurons

interneurons inhibit pyramidal neurons providing feedback inhibition

loops in cerebellum

Purkinje neurons are inhibitory and inhibit DCN

DCN excites the Inferior olive cell that feeds back and excites DCN and Purkinje neurons