(OBJ) Describe the concept that the hypothalamus is the primary site where there is integration of multiple forms of afferent information (e.g., sensory, affect) and subsequent modulation of multiple forms of efferent information (e.g., autonomic nervous system, pituitary) to promote adaptive behavior and homeostasis.
Key center in homeostasis
- -Integrative center for endocrine, autonomic, and somatomotor systems
- -Modulates affective behavior
Receives:
–Sensory info from entire body
–Visceral, olfactory, and retinal inputs
–Steroid & peptide hormone input
Contains sensor neurons that compare incoming sensory info to set points -> respond to changes in physiological state
Coordinates physiologic and cognitive aspects of emotion (via amygdala)
(OBJ) Describe the anatomical landmarks of the brain that demarcate the hypothalamus.
Forms ventral half of diencephalon Surrounds third ventricle Inferior = pituitary (via infundibulum) Anterior = optic chiasm --Merges with basal olfactory area --Continuous with preoptic area (POA) Posterior = mammillary bodies --Merges into periaqueductal grey and tegmentum Dorsal = thalamus Lateral/caudal = subthalamic region
What is the median eminence of the hypothalamus?
The raised area on the tuber cinereum that goes on to form the infundibulum
Contains the primary capillary network of the hypophysial portal system
What is the tuber cinereum?
“Grey swelling” on ventral surface of brain
Between the optic chiasm and mammillary bodies
From which six general areas does the hypothalamus receive input?
Septal nuclei and neighboring forebrain Hippocampus Amygdala Orbital/frontal cortex Retina Brainstem and spinal cord
True/false: Connections to the hypothalamus are normally one directional.
FALSE. Connections to hypothalamus are most often reciprocal.
Also, single neurons are multifunctional and not well organized.
(OBJ) Describe the three MAJOR afferents of the hypothalamus and the type of information these tracts carry.
(many are bidirectional)
- Limbic (emotion) - from hippocampus and amygdala
- -Medial forebrain bundle
- -Fornix
- -Stria terminalis - Brainstem/spinal cord (sensory information)
- -Median forebrain bundle
- -Dorsal longitudinal fasciculus - carries almost everything - Retina (sensory)
- -Retinohypothalamic tract
(OBJ) Describe the MAJOR efferents of the hypothalamus and the type of information these tracts carry.
(many are bidirectional)
- Limbic (emotion)
- -Mammillothalamic tract
- -Stria terminalis -> amygdala
- -Median forebrain bundle - Reticular system (autonomic control)
- -Mammillotegmental tract - Autonomic
- -Median forebrain bundle
- -Dorsal longitudinal fasciculus -> brainstem and spinal cord - Endocrine (to pituitary)
- -Supraopticohypophyseal tract: SO and PVN of hypothalamus -> AVP + oxytocin -> posterior pituitary (neurohypophysis)
- -Tuberoinfundivular tract: influence hormonal release from anterior pituitary (adenohypophysis)
(OBJ) Describe the nuclei and hormones that provide input to the posterior pituitary.
NUCLEI:
- -Paraventricular nucleus - parvocellular neurons
- -Supraoptic nucleus - magnocellular neurons
HORMONES: generally neuropeptides
- -Oxytocin - associated with parturition and milk secretion; the “love” hormone
- -Arginine vasopressin (AVP) - water reabsorption
(OBJ) Describe the role of oxytocin and arginine vasopressin in basic physiology (water reabsorption, changes associated with parturition) and in affiliative behaviors.
–Oxytocin - associated with parturition and milk secretion, sexual stimulation, uterine dilation, nursing, and stress; the “love” hormone (affiliative behaviors): trust, empathy, generosity, making eye contact, healthy long-lasting interpersonal relationships
–Arginine vasopressin (AVP) - functions in water reabsorption
(OBJ) Describe the difference between activational and organizational effects of steroids.
Activational effects: TRANSIENT actions that are essential for the control of reproduction
- -Onset of puberty
- -Maintenance of reproductive competence
- -Also implicated in PMS, PMDD, postpartum depression
Organizational effects: act early in neonatal development and later during adolescence to impart PERMANENT changes in neural structures that underlie many of the SEXUALLY DIFFERENTIATED aspects of the brain and behavior
- -SDN-POA (sexually dimorphic nucleus of the preoptic area): larger and darker in males (or females given androgens in the critical perinatal period) because there are more neurons
- -Sex behavior differences: male SDN-POA = mounting, vs female SDN-POA = arching of back
(OBJ) Describe the HPG axis (GnRH, FSH, LH).
GnRH (hypothalamus): neurons in periventricular region of medial POA and hypothalamus
- -Have bursting behavior dictated by both presynaptic inputs and intrinsic properties -> PULSATILE release
- -Do not express steroid hormone receptors
- > FSH/LH (gonadotropes in anterior pituitary) -> (sex hormones) testes, ovaries, other -x-> anterior pituitary and hypothalamus
- -High levels of sex hormone receptors in hypothalamus (and preoptic area)
(OBJ) Describe how gonadal steroids (estrogens, progestins, androgens) and other environmental factors (e.g., leptin) influence GnRH neurons through presynaptic afferents such as kisspeptin neurons.
Kisspeptin neurons receive input from sex hormones and from leptin, then release kisspeptin, which acts on GnRH hormones
–Sex hormones and leptin do NOT act directly on GnRH hormones
(OBJ) Name the nucleus that is the master regulator of circadian rhythms and describe how loops of transcription factor expression control “the clock”.
Nucleus: suprachiasmatic nucleus
- -Both necessary and sufficient to generate circadian rhythmicity
- -Receives direct input from retina (light very important)
- (indirect)-> pineal gland (regulates melatonin secretion)
- -also -> many other regions of hypothalamus (PVN, VMN, LHA) for circadian control of sleep, energy homeostasis, body temperature, reproduction, psychomotor performance, arousal, sensory perception
TF Loops: TFs (CLOCK/BMAL) form heterodimers -!-> txn of other genes (Per/Cry) -x-> CLOCK/BMAL -x!-> Per/Cry -x!x-> CLOCK/BMAL (starts over)
- -Don’t need to know names, just that you have a cycle of heterodimers that turn on and off each other’s expression that allows a self-continuing loop
- -You don’t override the periodicity, just shift the phase (always 24 hours)
(OBJ) Describe the origin of leptin and how it regulates neural circuits in the hypothalamus to regulate energy homeostasis.
LEPTIN: produced in white adipose tissue in proportion to energy stores
- -Signals through JAK/STAT pathway via long form of receptor
- -Reaches brain through break in BBB by hypothalamus or area postrema, or through active transport
- -Acts in LHA and VTA (NPY/AgRP and POMC) - have two opposing systems that talk to each other; one decreases food intake, the other increases food intake; leptin acts on both
Discuss hypothalamic nuclei involved in feeding and satiety.
VMN/Arcuate nucleus (satiety center) - decrease food intake
–VMN key in resisting high-fat diet induced obesity
LHA (feeding center) - increase food intake; wakefulness
(this is an oversimplification)
True/false: the primary role of leptin is to diminish energy intake under conditions of adequate or more than adequate fat reserves
FALSE! The primary evolutionary role of leptin is to spur the body to maintain adequatefat stores in the absence of nutritional deficit.
(OBJ) Describe the routes other than leptin by which peripheral information on energy state reaches the hypothalamus.
Orexigenic peptides:
NPY: most orexigenic peptide known
Orexin: degeneration of orexin neurons -> narcolepsy; regulates thermogenesis in brown fat
AgRP
Anorexigenic peptides:
- -POMC: precursor for melanocortins
- -alpha-MSH
GI/Pancreatic hormones: CCK, ghrelin, insulin
- -Gives acute information about GI fill
- -Vagal afferents to NST
(OBJ) Define the genetic deficit in ob/ob and db/db mice.
ob/ob = obese; mutation in leptin gene
db/db = diabetes; mutation in leptin receptor gene
(OBJ) Describe the dysregulation in leptin homeostasis in obese individuals and why clinical trials with leptin have had such a low success rate.
1-2% of people have leptin (or leptin receptor) mutations
In obese people, leptin is elevated, but have peripheral and central (CNS) leptin resistance
- -Giving leptin has a modest and variable effect because of this
- -Reduced transport across the BBB + reduced signaling capacity in brain (less important)
(OBJ) Describe the location of orexin neurons in the hypothalamus and their role in arousal.
Located in lateral hypothalamic area
–Project to ENTIRE CNS
Two different peptides derived from same gene, act through GPCRs
Critical regulator of sleep/wake transitions
Also excited by decreased leptin/increased ghrelin
–Act as a primary sensory of energy homeostasis
–Negative energy balance (hunger) -> arousal
(OBJ) Describe the pathophysiological basis for narcolepsy.
Arises from loss of orexin neurons (neurodegenerative)
