Notes

The Nervous System - Overview

Introduction: Why Do We Need to Know the Brain?

"There has been one striking and totally unexpected behavioral result: a grave loss of recent memory in those cases in which the medial temporal-lobe resection was so extensive as to involve the major portion of the hippocampal complex bilaterally ... in [H.M.] ... the loss was immediately apparent. After operation this young man could no longer recognize the hospital staff nor find his way to the bathroom, and he seemed to recall nothing of the day-to-day events of his hospital life... However, his early memories were apparently vivid and intact."

The bilateral removal of the hippocampal formation and allied structures caused a severe form of anterograde amnesia.

The Nervous System: Overview and Terminology Nervous System

• Central Nervous System (CNS)
  • Brain
  • Spinal Cord
• Peripheral Nervous System (PNS)
  • Somatic and Autonomic Nervous System

White & Grey Matter in the Brain

Grey Matter of the Cortex

Korbinian Brodmann described in 1909 areas of the cerebral cortex on the basis of cytoarchitectural criteria. Areas differ in cell-types, layering and cell distribution, resulting in 52 Brodmann Areas.

Examples: Brodmann Area 3,1,2 Primary Somatosensory Cortex S1, Brodmann Area 17 Primary Visual Cortex V1.

Cerebral Convolutions: Species Differences

• Gyrencephalic (Human, Elephant).
• Lissencephalic (Rabbit, Mouse) (No gyrus structures). Lissencephaly in Humans is due to a defective migration during early to mid-gestation (12^th^ to 24^th^ weeks), leading to impaired development of gyri and sulci.

White Matter: Macroscopic

• Association Fibers (Green) link cortical areas of the same hemisphere. Arcuate fibers run over short distances, long-distance association fibers have names, such as the Superior and Inferior Longitudinal Bundle/Fasciculus, the Cingulum and Uncinate Bundle.
• Commissural Fibers (Red) link areas of the two hemispheres (Corpus Callosum, Anterior Commissure, Posterior Commissure).
• Projecting Fibers (Blue) link the cortex with subcortical areas of the brain and the spinal cord (e.g., Internal Capsule).

White Matter: Microscopic

• Oligodendrocytes
• Microglia
• Astrocytes

Telencephalon

Telencephalon: Basal Ganglia

The basal ganglia are the principal subcortical components of a family of neuronal circuits which link the thalamus and cerebral cortex. The basal ganglia are crucial for the initiation and modulation of voluntary movement by sending their output to the motor cortex via the thalamus. In addition, the basal ganglia also contribute to a variety of behavioral and cognitive function other than voluntary movement.

Basal Ganglia: Striatum In humans (and most primates), the striatum consists of three major subdivisions: the caudate nucleus, the putamen, and the nucleus accumbens. In rats and mice, the striatum is typically divided into two subdivisions: the caudate putamen, which is often referred to as the "dorsal striatum" (and which would correspond to the human caudate nucleus + putamen); and the nucleus accumbens, which is referred to as the "ventral striatum". The striatum is the major recipient of inputs from the substantia nigra, cerebral cortex, thalamus and brain stem. Striatal neurons, which are primarily GABAergic spiny neurons (90/95%), send afferent projections to the globus pallidus and reciprocal projections to the substantia nigra.

Basal Ganglia: Globus Pallidus The globus pallidus lies medial to the putamen and is divided into external and internal segments. The globus pallidus give rise to the major output projections from the basal ganglia:

• The Internal Segment (GPi) sends projections to the thalamus and pedunculopontine nucleus (a group of cells located in the brain stem).
• The External Segment (GPe) sends projections to the internal segment of the globus pallidus and to the subthalamic nucleus.

Basal Ganglia: Substantia Nigra The substantia nigra is a midbrain (mesencephalon) structure, which contains a dense population of dopamine cells. The substantia nigra can be subdivided into substantia nigra pars compacta and pars reticulata. Dopamine cells in the substantia nigra pars compacta project to dorsal parts of the striatum (in humans: to caudate nucleus and dorsal part of putamen; in rats and mice: to caudate putamen), forming the nigrostriatal dopamine pathway.

Disorders of the Basal Ganglia: Parkinson's Disease Parkinson's disease is a chronic and progressive degenerative disease of the brain that impairs motor skills, speech, and other functions. In patients with Parkinson's disease, the dopaminergic cells in the substantia nigra pars compacta are lost.

Telencephalon: Limbic System

Limbic System: Hippocampal Formation In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problems (especially spatial memories) and disorientation appear among the first symptoms. People with extensive, bilateral hippocampal damage (such as in patients with progressed AD) may experience anterograde amnesia - the inability to form or retain new memories.

Limbic System: Amygdalar Complex Functional involvement of amygdala in emotions. Human brain activity (measured by functional MRI) in response to emotional stimuli.

Diencephalon

Diencephalon: Overview Thalamus and Hypothalamus are the two main structures that constitute the Diencephalon. The main function of the Epiphyse or Pineal Gland is the production of melatonin. The Chiasma Opticum is the location where the optic nerves cross.

Diencephalon: Thalamus

• It receives inputs and sends outputs to various regions of the brain.
• It represents the "Gatekeeper of the brain".
• It is important for the transfer of information from the periphery to sensory processing regions in the telencephalon.
• It has important gating (filtering) functions: it determines whether sensory information reaches conscious awareness in the neocortex.
• It participates in the integration of motor information from the cerebellum and basal ganglia and transmits this information to cerebral areas concerned with movement.

Diencephalon: Hypothalamus

• It regulates several behaviors that are essential for homeostasis and reproduction: it controls a variety of bodily and reproductive functions, including growth, eating, drinking and maternal behavior, by regulating hormonal secretions from the pituitary gland.
• It is an important control center for the autonomic nervous system and for the hypothalamus-pituitary-adrenal (HPA) stress-response system.

Diencephalon: Neuroendocrinology of the Hypothalamus

Diencephalon: epithalamus and Subthalamus Epithalamus

• Epithelial roof of the third ventricle, habenula, pineal body and afferent/efferent connections.
• Secretion of melatonin, regulation of day-night cycles, information processing related to olfaction.

Subthalamus

• Continuation of the tegmentum.
• Functionally part of the basal ganglia (motor control).

Brain Stem, Cerebellum & Spinal Cord

Mesencephalon: Overview A structure that can be found above the brain stem. Colliculus Superior and Colliculus Inferior are a pair of nuclei that together form the reflexes associated with vision.

Mesencephalon: Functional Units

1. Tectum (roof)
   • Superior Colliculus: visual and oculomotor reflexes.
   • Inferior Colliculus: relay auditory tract.
2. Tegmentum (floor)
3. Reticular formation: automatic processing of incoming sensation and outgoing motor commands, helps to maintain consciousness, can initiate motor response to stimuli (see also medulla oblongata! Reflex center, some sensory information is directly processed in this area and sends motor commands even before consciousness).
4. Red Nucleus: involuntary control of background muscle tone and limb posture.
5. Substantia Nigra: regulates activity in the basal nuclei, degeneration of dopaminergic cells causes Parkinson's disease.
6. Cerebral Peduncles: connect primary motor cortex with motor neurons in brain and spinal cord, carry ascending sensory information to thalamus.
7. Ventral Tegmental Area (VTA): part of the limbic system, projects e.g. to Nucleus Accumbens and Amygdala, emotional reinforcement and reward function.

Pons: Overview

It is a collection of nuclei and fibers that form a bridge for information coming from one part of the brain and is relayed on the other side.

• Pontine Nuclei receive fibers from all cortical areas and relay to the contralateral cerebellum.
• Locus Coeruleus ("blue spot") contains noradrenergic cells innervating large portions of the brain, mediating physiological response to panic and stress. (secretion of neuroadrenaline).

Medulla Oblongata: Overview

It is part of the brain stem, containing fiber tracks (group of axons).

• Pyramid: contains descending cortico-spinal fibers.
• Olive: relay nucleus for afferent connection from motor cortex and red nucleus, efferent to contralateral cerebellum.
• Reticular Formation: (entire brain stem!) containing the raphe nuclei and magno/parvocellular nuclei, which regulate respiration, circulation, vomiting, swallowing, and pain control. (Without necessarily reaching the conscious level).
• Reflex Centers: for heart and circulation (vasomotor/cardiac) and respiratory rhythmicity. (Without necessarily reaching the conscious level).

Cerebellum: Overview It is important for voluntary movement, posture, equilibrium and motor control.

Spinal Cord: Segmental organization

From each segment 2 spinal nerves are originated. The Radix Posterior (afferent) dorsal root brings input from the periphery to the spinal cord. The Radix Anterior (efferent) ventral root brings motor information from the spinal cord to the periphery.

Spinal Cord: Grey Matter

The grey matter of the spinal cord consists of cell bodies of interneurons, motor neurons and synaptic connections. Fibers of the motor neurons in the ventral horn leave the spinal cord efferent/motor commands to muscles. Afferent/sensory axons enter through the dorsal horn and either synapse on sensory interneurons in the dorsal horn, or join the ascending tracts in the white matter.

Spinal Cord: White Matter

The white matter of the spinal cord mostly consists of myelinated axons of motor and sensory neurons organized in columns (containing several fiber tracts) carrying information to (afferent/ascending) and from (efferent/descending) the brain.

Cranial Nerves, Meninges, Ventricles & Cerebrospinal Fluid

Cranial nerves: Overview Cranial nerves are the nerves that emerge directly from the brain (mostly from the brainstem), in contrast to spinal nerves (which emerge from segments of the spinal cord). Cranial nerves are generally named according to their structure or function. They usually innervate areas close to where they are originated from. The cranial nerves provide motor and sensory innervation mainly to the structures within the head and neck. The sensory innervation includes sensation such as temperature and touch, and innervation such as taste, vision, smell, balance and hearing. The Vagus Nerve (X) provides sensory and autonomic (parasympathetic) innervation to most of the organs in the chest and abdomen. (It doesn't innervate the head/neck area).

Meninges: Overview

The Meninges are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in the subarachnoid space between the arachnoid mater and the pia mater.

• Dura Mater
  • Leather-like, inflexible layer surrounding the CNS and spinal cord.
  • Inner and outer layers, containing large venous sinuses (large veins that bring the blood back to the heart) (e.g., superior sagittal sinus).
• Arachnoid Mater
  • Loose connective tissue bridging the liquor-filled space (subarachnoidal space) between dura mater and pia mater.
  • Contains all larger blood vessels.
• Pia Mater
  • Translucent, thin membrane directly covering the entire surface of the brain, follows all sulci and gyri.

Ventricles: Overview They are cavities containing fluid.

• Lateral Ventricles (Cerebral Hemispheres)
• 3rd Ventricle (Diencephalon)
• Aequaductus Mesencephali (Mesencephalon)
• 4th Ventricle (Pons, Midbrain)
• Central Canal (Spinal Cord).

Ventricles: Pathologies

• Neurodevelopmental Disorders (e.g., Schizophrenia).
• Neurodegenerative Disorders (e.g., Alzheimer's Disease, AD).

Cerebrospinal Fluid: Overview

• It is a clear fluid, high content of NaCl, contains glucose and K+, low in proteins, very few cells (lymphocytes).
• It does a turnover three times a day.
• It flows throughout the ventricular system ad is absorbed back into the bloodstream (via blood-brain-barrier).

Cerebrospinal Fluid: Main Functions

• Buoyancy: the actual mass of the human brain is approx. 1.5kg, however, the net weight of the brain suspended in the CSF is equivalent to a mass of 25gr. The brain therefore exists in neutral buoyancy, which allows the brain to maintain its density without being impaired by its own weight, which could cut off blood supply.
• Protection: CSF protects the brain tissue from injury when jolted or hit. In addition, it helps regulating intracranial pressure (lowering CSF production can help preventing brain ischemia).
• Homeostasis: through absorption back into the blood stream, CSF can rinse "metabolic waste" from the CNS allowing for a homeostatic regulation of the brain.

Cerebrospinal Fluid: Pathologies Hydrocephalus

• Abnormal accumulation of CSF within the brain.
• Congenital (neurodevelopmental disturbances) or acquired postnatally.
• Most common cause: Aqueductal Stenosis (mesencephalic passage between 3^rd^ and 4^th^ ventricles is blocked or too narrow to allow sufficient cerebral spinal fluid to drain fluid accumulates in the upper ventricles).

Cerebral Circulation The brain is one of the most metabolically active organs in the body!

• It uses approx. 20-25% of the body's total energy requirements (despite accounting for only 2% of the body's mass).
• The brain stores little energy as glycogen and relies mostly on circulating glucose.
• The rate of the cerebral blood flow in the adult is typically 750 milliliters per minute, representing 15% of the cardiac output.

Cerebral Circulation: Arteries Main branches of the internal carotids

• Anterior Cerebral Artery
• Middle Cerebral Artery

Main branches of the vertebral/basilar arteries

• 3 arteries supplying the cerebellum
• Posterior Cerebral Artery.

Cerebral Circulation: Veins

Brain Evolution & Cross - Species Comparison

Absolute and Relative Differences

Brain Mass versus Body Mass

Encephalization Quotient (EQ)

It describes brain size as a ratio of the expected average brain size relative to the actual body weight. Some scientists argue that EQ correlates with the intelligence of a species. Einstein:

• Average (or even smaller) total brain size
• Smaller neuron/glia ratio than average.

"Our results also suggest that Einstein had relatively expanded prefrontal cortices, which may have provided underpinnings for some of his extraordinary cognitive abilities, including his productive use of thought experiments. From an evolutionary perspective, the specific parts of Einstein's prefrontal cortex that appear to be differentially expanded are of interest because recent findings indicate that these same areas increased differentially in size and became neurologically reorganized at microanatomical levels during hominin evolution in association with the emergence of higher cognitive abilities.

Brain Evolution in View of Cortical Expansion

Cortical expansion is often equated with"brain evolution", whereby the relative size of the cerebral cortex increases while the relative size of the cerebellum remains fairly constant. Human cortical expansion is relative but does not affect each region similarly!

Cortical Expansion of Associative Areas

Prefrontal Cortex: Human vs. Rats Human Prefrontal cortex functions: Planning, Attention, Working Memory, Cognitive Flexibility and Impulsivity. Do rats have similar prefrontal structures and functions?

Assessment of Human prefrontal Cortical Functions

Example: Working Memory

• Short-term memory buffer with limited temporal capacity.
• Used to hold relevant information "online" in order to guide ongoing behavior, including strategic planning and problem solving.

Cognitive tasks which demand working memory activate the PFC: an fMRI investigation in humans

Assessment of Rat Prefrontal Cortical Functions

Effects of prefrontal cortex lesion on working memory in the 8-arm radial arm maze. Lesions to the medial part of the prefrontal cortex (mPFC) lead to working memory impairments as evident by the increased number of working memory errors in the 8-arm radial arm maze.

Prefrontal Cortex: Human vs. Rats The rodent prefrontal cortex (PFC) is not as anatomically complex as the primate; however, many of the critical neuroantomical and functional characteristics are preserved in rodents, which allow meaningful cross species comparisons relevant to study of the neurocognitive and neurobiological mechanisms that underlie changes in executive functioning across the lifespan. As indicated in the figure, the medial portion of rodent PFC (which includes anterior cingulate (aCg), prelimbic (PL), and infralimbic (IL) cortices) shares strong anatomical homology with primate dorsolateral PFC.

Cross-Species Comparison of Subcortical Areas

Cross-Species Comparison of Hippocampal Anatomy Schematic illustrations of the orientation of the hippocampal long axis in rats, macaque monkeys and human. The longitudinal axis is described as ventrodorsal in rodents and as anteroposterior in primates. Note that a 90° rotation is required for the rat hippocampus to have the same orientation as that of primates.

Cross-Species Comparison of Hippocampal Functions "Recalling Routes around London: Activation of the Right Hippocampus in Taxi Drivers" Positron Emission Tomography (PET) was used to examine the neural substrates of spatial memory retrieval in licensed London taxi drivers while they recalled complex routes around the city.

Activity in the human brain related to spatial navigation. (a) A virtual town was shown on a computer monitor, and subjects in a PET imaging machine used buttons to navigate the virtual environment. (b) Increased brain activity associated with spatial navigation was observed in the right hippocampus (purple) and left tail of the caudate (green).

Effects of hippocampal lesions on reference learning and memory in the Morris water maze: deficits in the acquisition of spatial reference memory parallel the magnitude of dorsal hippocampal lesions, but is hardly present following ventral hippocampal lesions.

Cross-Species Comparison of Amygdalar Anatomy Primary amygdalar nuclei and basic circuit connections and function are conserved across species. An enlarged image of the basolateral complex of the amygdala (BLA) and central nucleus of the amygdala (CeA) or analogues are shown next to a coronal section from the brains of a lizard, rat, cat, monkey and human. In Post-Traumatic Stress Disorders (PTSD), the amygdala is hyperactive in response to negative (aversive) emotional stimuli vs. neutral and positive stimuli.

Experimental investigations of amygdalar functions in rodents.

Classical Fear Conditioning: Effects of complete electrolytic lesions of the amygdala.

Cross-Species Comparison of Basal Ganglia Anatomy