Kisspeptin, neurokinin B, and dynorphin (KNDy) neurons are

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

s in the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

of the brain that are central to the hormonal control of reproduction. KNDy neurons in the hypothalamus coexpress

kisspeptin Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human met ...

neurokinin B Neurokinin B (NKB) belongs in the family of tachykinin peptides. Neurokinin B is implicated in a variety of human functions and pathways such as the secretion of gonadotropin-releasing hormone. Additionally, NKB is associated with pregnancy in fe ...

(NKB) and

dynorphin Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin ...

. They are involved in the

negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and release ...

(GnRH) release in the hypothalamic–pituitary–gonadal (HPG) axis.

Sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

s released from the

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sperm ...

s act on KNDy neurons as inhibitors of kisspeptin release. This inhibition provides negative feedback control on the HPG axis. KNDy peptide colocalization was first discovered in 2007 in sheep and was later confirmed to be present in mice, rats, cows and nonhuman primates. KNDy neurons are thought to be located in the hypothalamus region of human brains due to conservation across most

mammalian Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

species. Other roles of KNDy neurons include influences on

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the p ...

production;

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. I ...

; stress' effects on

reproduction Reproduction (or procreation or breeding) is the biological process by which new individual organisms – "offspring" – are produced from their "parent" or parents. Reproduction is a fundamental feature of all known life; each individual or ...

; and the control of

thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

GnRH pulse regulation

KNDy neurons control

GnRH Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

pulse generation by through release of three known

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

(NKB),

and

. NKB and dynorphin are the two peptides that regulate the secretion of kisspeptin. NKB is the stimulating peptide that initiates the pulsatile release of GnRH by activating NKB receptors, called TACR3, on mutually connected KNDy neurons to release kisspeptin in an autocrine signalling pathway. Kisspeptin then activates the GPR54 receptors on GnRH neurons inducing the pulsatile release of GnRH and on KNDy neurons, adding to the stimulatory effect of NKB. Eventually the pulse is terminated by dynorphin, which acts on

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind o ...

s (KOR) in KNDy neurons to inhibit NKB and kisspeptin secretion and inhibits GnRH secretion acting directly on GnRH neuron receptors.

Sexual dimorphism in KNDy neuron populations

KNDy neurons are most densely located in the

arcuate nucleus The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...

(ARC) of the hypothalamus, but also exist in the rostral periventricular area of

third ventricle The third ventricle is one of the four connected ventricles of the ventricular system within the mammalian brain. It is a slit-like cavity formed in the diencephalon between the two thalami, in the midline between the right and left latera ...

(RP3V) and the

preoptic area The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular). Functions The preoptic area is responsible for ther ...

(POA). Expression of the KNDy peptides highlighted has been shown to differentiate between

species In biology, a species is the basic unit of Taxonomy (biology), classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of ...

sex Sex is the trait that determines whether a sexually reproducing animal or plant produces male or female gametes. Male plants and animals produce smaller mobile gametes (spermatozoa, sperm, pollen), while females produce larger ones (ova, ...

es, and with fluctuating

steroidal A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

hormonal levels. Improvements in

immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to ant ...

and deep-brain imaging techniques have revealed information about KNDy cell populations and

sexual dimorphism Sexual dimorphism is the condition where the sexes of the same animal and/or plant species exhibit different morphological characteristics, particularly characteristics not directly involved in reproduction. The condition occurs in most anim ...

. Larger populations appear in the female ARC than in the male ARC. The RP3V is composed of the anteroventral periventricular nucleus (APVN) and the preoptic periventricular nucleus, where KNDy neurons are sexually dimorphic. KNDy populations and sexual dimorphism appear in most species studied, including humans, but presence in the RP3V is primarily associated with

rodents Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are roden ...

, with similar sexual dimorphism.

Steroid hormone feedback

Negative feedback of steroid hormones in both males and females controls the pulsatile nature of

secretion, subsequently increasing or decreasing the release of LH and FSH from the anterior pituitary. This is mediated by estrogen receptor α (ERα), expressed on KNDy neurons. The binding of

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristic ...

to this receptor in the ARC region inhibits KNDy neurons and therefore prevents GnRH release. KNDy neurons are involved in positive feedback of the

HPG axis HPG may refer to: * Huppuguda railway station, in Hyderabad, India * Hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to ...

. This mechanism is best exemplified by the

LH surge Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...

in the female reproductive cycle, where the increase of estrogen from the growing ovarian follicle causes positive feedback in the AVPV region, and subsequently a rise in LH from the pituitary.

References

{{Reflist, 30em Endocrine system Human female endocrine system Hypothalamus Limbic system Neuroendocrinology Neurons