Neuroanatomy and Neurophysiology Pharmacy Biomedical Preview July 7, 2015 Jeremy J. McLemore Howard University College of Pharmacy Pharm D Candidate, Class of 2017 APhA | SNPhA | ASHP | ΦΛΣ | KΨ

Anatomical Orientations Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

Terminology – Ganglia vs nucleus – Tract vs nerve – White matter vs grey matter – Medial vs lateral – Ipsilateral vs contralateral? Planes of section – Coronal – Sagittal – Horizontal (axial) – Tangential

Autonomic Nervous System Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA. Central vs Peripheral Nervous System Somatic Nervous System

Major divisions of the CNS Prosencephalon (forebrain) – Telencephalon Cerebral cortices, basal nuclei, limbic system – Diencephalon Thalamus, hypothalamus Mesencephalon (midbrain) – Tectum, tegmentum Rhombencephalon (hindbrain) – Metencephalon Pons, cerebellum – Myelencephalon Medulla Spinal Cord Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

External Features of the CNS

Cerebral cortex is convoluted, creating sulci (grooves) and gyri (bumps) These foldings are – fairly well preserved across individuals – functionally segregated (Brodmann’s areas) – used as landmarks to partition the cerebral cortex into lobes Lateral Surface Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

Ventral surface (cut at midbrain) Peel back temporal lobe to expose insular cortex and transverse temporal gyri Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

Midsagittal view reveals midline structures, subcortical areas and interhemispheric pathways Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

tonsil Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA. Cerebellum

Inferior cerebellar peduncle Middle cerebellar peduncle Superior cerebellar peduncle Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

12 cranial nerves responsible for the sensory, motor and autonomic function of the face area as well as descending pathways involved in autonomic function Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

CN I – Olfaction CN II – Vision CN III, IV, VI – Eye movements CN V – Sensation from the face/oral cavity/teeth and muscles of mastication CN VII – Muscles of facial expression, salivary glands, taste from anterior 2/3 of tongue CN VIII – Auditory and vestibular CN IX – Pharyngeal musculature, salivary glands, taste from posterior 1/3 of tongue CN X – Major visceral sensory/motor nerve, pharyngeal musculature, taste from back of throat CN XI – Neck and shoulder muscles (sternocleidomastoid and trapezius) CN XII – Tongue muscles

Organization of the spinal cord Cervical (7 vertebra, 8 nerves) Thoracic (12 vertebra, 12 nerves) Lumbar (5 lumbar vertebra, 5 nerves) Sacrum/coccyx (5 sacral nerves and 1 coccygeal)

Ventricles Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA. Choroid plexus within the ventricular system makes cerebral spinal fluid (CSF) CSF diffuses within the ventricles and central canal to the subarachnoid space (via foramen of Magendie and Luschka) eventually dumping into the venous system via sinuses Lateral View Superior View

Meninges Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

Neurodevelopment

Gastrulation Formation of the primitive streak initiates gastrulation and the formation of 3 germ layers (ectoderm, mesoderm, and endoderm) Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier. Neural Induction Directing proneural regions of the ectoderm into the neural plate

Neurulation Folding (neural groove) and fusion of the neural plate to form the neural tube Fusion around future cervical region ~ED20 and “zips” anterior and posterior Anterior neuropore closes ~ED24 Posterior neuropore closes ~ED25/26 Secondary neurulation at sacral and coccygeal segments ~ED20-42 Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

Vesicle Formation Primary vesicle formation Cephalic and cervical flexure partition prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) Secondary vesicle formation Pontine flexure partitions rhombencephalon into myelencephalon (medulla) and metencephalon (cerebellum) Telencephalic flexure divides prosencephalon into diencephalon and telencephalon (prosencephalization) ~E week 4.75 ~E week 6 ~E week 6.5 Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

Cortical Histogenesis and Migration In cortical areas, additional layers develop, resulting in further thickening The progenitor processes are no longer able to support radial migration via somal translocation Therefore, radial glia are utilized for migration of neurons into the cortical plate These neurons settle in inner regions of the cortical plate first (inside-out development) Fundamental Neuroscience for Basic and Clinical Applications, D.E. Haines (editor), 3 rd edition, 2006, Churchill Livingstone Elsevier Publishing, Philadelphia, PA.

How do all these changes take place? Translational research has helped us understand the integrative nature of these processes (e.g. organizers and inducers) Tissue explants and transplants were used to determine how these processes work in isolation versus in the presence of the surrounding tissue With advancements in molecular biology and genetics, we can now directly test the influence of specific genes and signaling molecules Drosophila unfortunately, no Nobel prize Hans Spemann, PhD Nobel prize in Physiology/Medicine 1935

The regional development of the CNS emerges through the interplay of signaling molecules, DNA-binding proteins (transcription factors), and genes It is the graded and temporal expression of these molecules and their effects on gene transcription that determine regional identities Let’s take a look at some experiments that demonstrate this interplay and some genes and molecules involved

Neural Induction Removal of ectodermal tissue prior to gastrulation results in epidermal induction Removal of ectodermal tissue during gastrulation results in neural induction Therefore, neural induction begins during gastrulation and the presence of other germ layers are important Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier.

Neural Induction The blastopore region was taken from a pigmented frog embryo and implanted in a non-neurogenic region of a non- pigmented host A second neuroaxis was created demonstrating that this region of the mesoderm is important for germ layer formation and neural induction Furthermore, the secondary neuroaxis contained non-pigmented cells, suggesting that the implanted region “organized” the non-neurogenic host region Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier.

Dorsal/Ventral Patterning The sulcus limitans is a useful landmark that divides the dorsal alar plate (sensory) from the ventral basal plate (motor). How does this happen? Presence of notochord (mesoderm origin) results in ventralization of neural tube (motor neurons) Removal of notochord results in a lack of ventralization Transplanting additional notochord ventralizes tissue Therefore, initial ventralizing signal comes from non- ectodermal tissue (mesodermal notochord) Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier.

Dorsal/Ventral Patterning Sonic hedgehog (Shh) – Homolog of hedgehog (hh) in Drosophila – Signaling protein expressed first in the notochord and then in ventral floorplate – Ventralizes the neural tube Bone morphogenic proteins (BMPs) and Wnts (homolog of wingless gene in drosophila) – Expressed in the developing ectoderm and dorsal neural tube Dorsal/ventral patterning is dependent on the anatagonizing actions of these (and even other) signaling molecules The boundary between these antagonizing forces becomes the sulcus limitans Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier.

Hindbrain Segmentation Rhombomeres (R1-8) – Repeated morphological subdivisions of the hindbrain Homeobox genes (Hox) – DNA regions that code for transcription factors Hox gene expression corresponds to rhombomere boundaries and are involved in differentiating these divisions Hoxa1 gene knockout mice demonstrate the importance of regional segmentation due to the effects on R4/5 (abducens and facial nerve) Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier.

Forebrain Segmentation Prosemeres (P1-6) correspond to regions within prosencephalon Emx1 and emx2 genes are present in the rostral and caudal divisions, respectively Emx and Pax genes thought to contribute to forebrain segmentation similarly to how hox genes regulate rhomobencephalon segmentation Development of the nervous system. Sanes DH, Reh TA, Harris WA, editors. 2 nd edition, 2006, Elsevier.