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How Herpesvirus Invades Nervous System


Northwestern Medicine scientists have identified a component of the herpesvirus that “hijacks” machinery inside human cells, allowing the virus to rapidly and successfully invade the nervous system upon initial exposure.

Led by Gregory Smith, associate professor in immunology and microbiology at Northwestern University Feinberg School of Medicine, researchers found that viral protein 1-2, or VP1/2, allows the herpesvirus to interact with cellular motors, known as dynein. Once the protein has overtaken this motor, the virus can speed along intercellular highways, or microtubules, to move unobstructed from the tips of nerves in skin to the nuclei of neurons within the nervous system.

This is the first time researchers have shown a viral protein directly engaging and subverting the cellular motor; most other viruses passively hitch a ride into the nervous system.

“This protein not only grabs the wheel, it steps on the gas,” says Smith. “Overtaking the cellular motor to invade the nervous system is a complicated accomplishment that most viruses are incapable of achieving. Yet the herpesvirus uses one protein, no others required, to transport its genetic information over long distances without stopping.”

Herpesvirus is widespread in humans and affects more than 90 percent of adults in the United States. It is associated with several types of recurring diseases, including cold sores, genital herpes, chicken pox, and shingles. The virus can live dormant in humans for a lifetime, and most infected people do not know they are disease carriers. The virus can occasionally turn deadly, resulting in encephalitis in some.

Until now, scientists knew that herpesviruses travel quickly to reach neurons located deep inside the body, but the mechanism by which they advance remained a mystery.

Smith’s team conducted a variety of experiments with VP1/2 to demonstrate its important role in transporting the virus, including artificial activation and genetic mutation of the protein. The team studied the herpesvirus in animals, and also in human and animal cells in culture under high-resolution microscopy. In one experiment, scientists mutated the virus with a slower form of the protein dyed red, and raced it against a healthy virus dyed green. They observed that the healthy virus outran the mutated version down nerves to the neuron body to insert DNA and establish infection.

“Remarkably, this viral protein can be artificially activated, and in these conditions it zips around within cells in the absence of any virus. It is striking to watch,” Smith says.

He says that understanding how the viruses move within people, especially from the skin to the nervous system, can help better prevent the virus from spreading.

Additionally, Smith says, “By learning how the virus infects our nervous system, we can mimic this process to treat unrelated neurologic diseases. Even now, laboratories are working on how to use herpesviruses to deliver genes into the nervous system and kill cancer cells.”

Smith’s team will next work to better understand how the protein functions. He notes that many researchers use viruses to learn how neurons are connected to the brain.

“Some of our mutants will advance brain mapping studies by resolving these connections more clearly than was previously possible,” he says.

Story Source:

The above story is reprinted from materials provided by Northwestern University, via EurekAlert!, a service of AAAS.

Journal Reference:

Sofia V. Zaichick, Kevin P. Bohannon, Ami Hughes, Patricia J. Sollars, Gary E. Pickard, Gregory A. Smith. The Herpesvirus VP1/2 Protein Is an Effector of Dynein-Mediated Capsid Transport and Neuroinvasion. Cell Host & Microbe, 2013; 13 (2): 193 DOI: 10.1016/j.chom.2013.01.009

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The Reticular Formation, Limbic System and Basal Ganglia

February 19, 2012 2 comments

The Reticular Formation

It’s a ‘diffuse net’ which is formed by nerve cells and fibers. It extends from the neuroaxis spinal cord through medulla, pons, midbrain, subthalamus, hypothalamus and thalamus (spinal cord is relayed superiorly to the cerebral cortex).

Many afferent and efferent pathways project in and out of the RF from most parts of the CNS. The main pathways through the RF is poorly defined and difficult to trace using silver stains. Reticular formation can be divided into three columns : median, medial and lateral columns.

Functions of the Reticular formation

1.   Control of skeletal muscles:

  • RF modulates muscle tone and reflex activities (via reticulospinal and reticulo bulbar tracts). It is important in controlling muscles of facial expression when associated with emotions.

2.   Control somatic and visceral sensation (influence can be excitatory or inhibitory)

3.   Control of autonomic nervous system

4.   Control of endocrine nervous system (hypothalamus and the pituitary)

5.   Influence on the biological clock (rhythm)

6.   The reticular activating system (arousal and level of consciousness are controlled by the RF)

Clinical note

When a person smiles for a joke, the motor control is provided by the RF on both side of the brain. The fibers from RF is separated from corticobulbar pathway (supply for facial muscles). If a patient suffers a stroke that involves corticobulbar fibers, he or she has facial paralysis on the lower part of the face, but is still able to smile symmetrically.

The Limbic System

 Limbic structures   Functions of the limbic system 
  1. Sub callosal, cingulated and parahippocampal gyri
  2. Hippocampal formation
  3. Amygdaloid nucleus
  4. Mammillary bodies
  5. Anterior thalamic nucleus
1. Influence the emotional behavior:a. Reaction to fear and angerb. Emotions associated with sexual behavior

2. Hippocampus is involved in converting short term memory to long term memory (If the hippocampus is damaged, patient is unable to store long term memory – Anterograde amnesia)

The  Basal Ganglia and their connections

Connections of the Basal Ganglia

Yellow arrow : Pallidofugal fibers

Caudate nucleus and the Putamen: main sites of receiving inputs

Globus pallidus: main site from which output leaves

Afferent and Efferent fibers

Connections of the caudate nucleus and Putamen Connections of the Globus pallidus
Afferent Efferent Afferent Efferent
CS: CorticostriateTS: Thalamostriate

NS: Nigrostriate

BS: Brainstem striatal fibers

SP: Striatopallidalfibers

SN: Striatonigral fibers

SP: Striatopallidalfibers Pallidofugalfibers

Functions of  the Basal Nuclei

Basal Nuclei controls muscular movements by influencing the cerebral cortex (it doesn’t have direct control through descending pathways to the brainstem and spinal cord). It helps to prepare for the movements (enables the trunk and limbs to be placed in appropriate positions before discrete movements of the hands and feet).

Functional connections of the Basal Nuclei and how they influence muscle activities

 
REFERENCES: 
1. Ben Greenstein, Ph.D, Adam Greenstein, BSc (Hons) Mb, ChB Color Atlas of Neuroscience
2. Allan Siegel Ph.D, Hreday N. Sapru Ph.D Essential Neuroscience, 1st Edition
3. Stanley Jacobson, Elliot M. Marcus Neuroanatomy for the Neuroscientist
4. Patrick f. Chinnery Neuroscience for Neurologists
5. Dale Purves Neuroscience, 3rd Edition
6. Suzan Standring Gray’s Anatomy
7. Keith L. Moore, Arthur F. Dalley, Anne M. R. Agur Clinically Oriented Anatomy
8. Frank H. Netter Atlas of Human Anatomy
9. Walter J. Hendelman, M.D., C.M. Atlas of Functional Neuroanatomy
10. Mark F. Bear, Barry W. Connors, Michael A. Paradiso Neuroscience Exploring the Brain
11. Dale Purves et al. Principles of Cognitive Neuroscience
12. Eric R. Kandel et al. Principles of Neural Science