The fasciculus retroflexus (FR) also known as the habenulointerpeduncular tract is a bundle of fibers located at the base of the midbrain in vertebrates. [1] [2] Connected to the habenula (Hbn) and the interpeduncular nucleus (IPN), the fasciculus retroflexus is involved in a variety of bodily phenomena, some being sleep retention. [3] and drug addiction. [4] It acts as a channel through which messages are sent between the stria medullaris and the mid- and hindbrain. The fasciculus retroflexus, along with the stria medullaris, the habenula, and the medial forebrain bundle forms a unit for the transfer of neurological impulses. In this unit, the fasciculus retroflexus mediates the transfer of information for processes such as pain, pleasure, and motor control [5]
The fasciculus retroflexus is the main efferent track of the habenula. The FR is an extremely condensed bundle of fibers which consists of two concentric regions. [4] The first of these is the inner fibers of the FR, beginning at the medial habenula and span to interpeduncular nucleus, sometimes referred to as the Hbn-FR-IPN complex. [6] The outer portion runs from the lateral habenula to the RMTg.
The FR functions as the connecting segment between the Hbn and IPN in the Hbn-FR-IPN complex. The function of these three portions are extremely interconnected in their neurological purpose. Signals sent from the habenula to the interpeduncular nucleus must first pass through the core of the fasciculus retroflexus.
The placement of the FR makes it a vital pathway for contribution to proper functioning of sleep-wake cycles (Circadian rhythm). The FR has significant influence on REM sleep, specifically. When FR function is hindered, REM sleep was reduced by more than 50% in a study done on rats. [3]
The habenula is largely identified as the reward center of the brain, and so a prime target for drug addiction. [4] [7] By association, the fasciculus retroflexus plays a key role in transmitting the messages which cause dependence on certain controlled substances. Many trials have been done specifically linking these connections to nicotine addiction. The basis of drug addiction is tether to the fluctuating levels of dopamine found in our brains. A key inhibitor, which functions to keep these dopamine levels in check, is GABA. The Hbn-FR-IPN makes up the main pathway through which both GABA and dopamine flow. Once drugs are introduced, this area of the brain, the reward and pleasure center is heavily involved. The inhibitory GABAergic cells are located in the nuclei of the RMTg, which is the output of the fasciculus retroflexus's inner portion. The modulation, activation, and inhibition of dopamine is mediated by the habenula and by association the inner and outer fasciculus retroflexus for the duration of drug use; this idea exemplifying its participation in the formation of drug addiction.
Early brain development of the fasciculus retroflexus, like most tissues of the central nervous system, persists when embryotic non-specified neural tissues begin to grow and differentiate. Both the fasciculus retroflexus and the habenula have been observed to be dependent of the presence Wnt1, [8] as shown in a rat study.
When FR are lesioned artificially, a reduction in signal transduction is observed. This leads to an understanding that, at least for specific neurons, [9] the FR is vital to the signaling pathways related to the habenula; further solidifying the proposed structure and function of the FR, proving that its core channel is necessary for response output. The study of these lesions leads to an understanding of how defects in a mammal's Hbn-FR-IPN complex, or more specifically their fasciculus retroflexus, could potentially lead to decreased response time and signal transduction; insinuating that defects hold consequences in the central nervous system. Likewise, since the FR was found to be such a vital part of habenula function, loss of functionality in the FR would lead to co-malfunction in the habenula, which has been found to cause imbalances leading to anxiety, depression, and even schizophrenia. [4] [9]
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.
Dextroamphetamine (INN:dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.
The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.
The ventral tegmental area (VTA), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.
The epithalamus is a posterior (dorsal) segment of the diencephalon. The epithalamus includes the habenular nuclei, the stria medullaris, the anterior and posterior paraventricular nuclei, the posterior commissure, and the pineal gland.
The habenula is a small bilateral neuronal structure in the brain of vertebrates, that has also been called a microstructure since it is no bigger than a pea. The naming as little rein describes its elongated shape in the epithalamus, where it borders the third ventricle, and lies in front of the pineal gland.
The septal area, consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum.
18-Methoxycoronaridine, also known as zolunicant, is a derivative of ibogaine invented in 1996 by the research team around the pharmacologist Stanley D. Glick from the Albany Medical College and the chemists Upul K. Bandarage and Martin E. Kuehne from the University of Vermont. In animal studies it has proven to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine and sucrose. It has also been shown to produce anorectic effects in obese rats, most likely due to the same actions on the reward system which underlie its anti-addictive effects against drug addiction.
Brain stimulation reward (BSR) is a pleasurable phenomenon elicited via direct stimulation of specific brain regions, originally discovered by James Olds and Peter Milner. BSR can serve as a robust operant reinforcer. Targeted stimulation activates the reward system circuitry and establishes response habits similar to those established by natural rewards, such as food and sex. Experiments on BSR soon demonstrated that stimulation of the lateral hypothalamus, along with other regions of the brain associated with natural reward, was both rewarding as well as motivation-inducing. Electrical brain stimulation and intracranial drug injections produce robust reward sensation due to a relatively direct activation of the reward circuitry. This activation is considered to be more direct than rewards produced by natural stimuli, as those signals generally travel through the more indirect peripheral nerves. BSR has been found in all vertebrates tested, including humans, and it has provided a useful tool for understanding how natural rewards are processed by specific brain regions and circuits, as well the neurotransmission associated with the reward system.
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,.
The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.
The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.The reward system motivates animals to approach stimuli or engage in behaviour that increases fitness. Survival for most animal species depends upon maximizing contact with beneficial stimuli and minimizing contact with harmful stimuli. Reward cognition serves to increase the likelihood of survival and reproduction by causing associative learning, eliciting approach and consummatory behavior, and triggering positively-valenced emotions. Thus, reward is a mechanism that evolved to help increase the adaptive fitness of animals. In drug addiction, certain substances over-activate the reward circuit, leading to compulsive substance-seeking behavior resulting from synaptic plasticity in the circuit.
The stria medullaris (SM), is a part of the epithalamus and forms a bilateral white matter tract of the initial segment of the dorsal diencephalic conduction system (DDCS). It contains afferent fibers from the septal nuclei, lateral preoptico-hypothalamic region, and anterior thalamic nuclei to the habenula. It forms a horizontal ridge on the medial surface of the thalamus on the border between dorsal and medial surfaces of thalamus. The SM, in conjunction with the habenula and the habenular commissure, forms the habenular trigone. It is considered to be the primary afferent of the DDCS.
The interpeduncular nucleus (IPN) is an unpaired, ovoid cell group at the base of the midbrain tegmentum. It is located in the mesencephalon below the interpeduncular fossa. As the name suggests, the interpeduncular nucleus lies in between the cerebral peduncles.
The central nucleus of the amygdala is a nucleus within the amygdala. It "serves as the major output nucleus of the amygdala and participates in receiving and processing pain information."
The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic nucleus which functions as a "master brake" for the midbrain dopamine system. This region was discovered by the researchers, M. Barrot, J.Kaufling and T. Jhou. It is poorly differentiated from the rest of the ventral tegmental area (VTA) and possesses robust functional and structural links to the dopamine pathways. Notably, both acute and chronic exposure to psychostimulants have been shown to induce FosB and ΔFosB expression in the RMTg; no other drug type has been shown to induce these proteins in the RMTg.
The neuronal acetylcholine receptor subunit alpha-5, or alpha-5 nicotinic acetylcholine receptor(α5 nAChR) also known as the α5 receptor is a type of ligand gated neuronal type subunit of the nicotinic acetylcholine receptor involved in pain regulation encoded in the human by the CHRNA5 gene. This receptor is commonly associated with nicotine addiction, immunotherapy, cancer, pain and attention.