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As a result, the ACC may regulate the autonomic and perhaps emotional reactions to events it is representing. This event-based control of autonomic tone by the ACC would likely arise during all types of cognitive and affective processes, without necessarily being critical for any of them.The anatomical relevance and functional significance of medial parts of the rodent frontal cortex have been intensely debated over the modern history of neuroscience. Early studies emphasized common functions among medial frontal regions in rodents and the dorsolateral prefrontal cortex of primates. Behavioral tasks emphasized memory-guided performance and persistent neural activity as a marker of working memory. Over time, it became clear that long-standing concerns about cross-species homology were justified and the view emerged that rodents are useful for understanding medial parts of the frontal cortex in primates, and not the dorsolateral prefrontal cortex. Here, we summarize a series of studies on the rodent medial frontal cortex that began with an interest in studying working memory in the perigenual prelimbic area and ended up studying reward processing in the medial orbital region. Our experiments revealed a role for a 4-8Hz “theta” rhythm in tracking engagement in the consumption of rewarding fluids and denoting the value of a given reward. Evidence for a functional differentiation between the rostral and caudal medial frontal cortex and its relationship to other frontal cortical areas is also discussed with the hope of motivating future work on this part of the cerebral cortex.The medial wall of the primate frontal lobe encompasses multiple anatomical subregions. Based on distinct neurophysiological correlates and effects of lesions, individual areas are thought to play unique roles in behavior. this website Further, evidence suggests that dysfunction localized to specific subregions is commonly found in different neuropsychiatric disorders. The neurobiological underpinnings of these disorders, however, remain far from clear. Here, to better understand the functions of medial frontal cortex (MFC) and its role in psychiatric disease, we focus on its functional organization. We describe the emerging pattern in which more dorsal regions subserve temporally extended cognitive functions and more ventral regions predominantly subserve affective functions. We focus on two specific domains, decision-making and social cognition, that require integration across emotion and cognition. In each case, we discuss the current understanding of the functions believed to depend on subregions of MFC as a stepping-stone to speculate on how they might work in unison. We conclude with an overview of how symptoms of certain psychiatric disorders relate to our understanding of MFC functional organization and how further discovery could fuel advances in circuit-based therapies.The hippocampal region receives a dense serotoninergic innervation originating from both medial and dorsal raphe nuclei. This innervation regulates hippocampal activity through the activation of distinct receptor families that are expressed in excitatory and inhibitory neurons, terminals of several afferent neurotransmitter systems, and glial cells. Preclinical and clinical studies indicate that hippocampal dysfunctions are involved in learning and memory deficits, dementia, Alzheimer’s disease, epilepsy and mood disorders such as anxiety, depression and post-traumatic syndrome disorder, whereas the hippocampus participates also in the therapeutic mechanisms of numerous medicines. Not surprisingly, several drugs acting via 5-HT mechanisms are efficacious to some extent in some diseases and the link between 5-HT and the hippocampus although clear remains difficult to untangle. For this reason, we review reported data concerning the distribution and the functional roles of the 5-HT receptors in the hippocampal region in health and disease. The impact of the 5-HT systems on the hippocampal function is such that the research of new 5-HT mechanisms and drugs is still very active. link2 It concerns notably drugs acting at the 5-HT1A,2A,2C,4,6 receptor subtypes, in addition to the already existing drugs including the selective serotonin reuptake inhibitors.The subthalamic nucleus (STN) houses a dense cluster of glutamatergic neurons that play a central role in the functional dynamics of the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. Numerous anatomical, electrophysiological, neurochemical and behavioral studies have reported that serotonergic neurons from the midbrain raphe nuclei modulate the activity of STN neurons. Here, we describe this serotonergic innervation and the nature of the regulation exerted by serotonin (5-hydroxytryptamine, 5-HT) on STN neuron activity. This regulation can occur either directly within the STN or at distal sites, including other structures of the basal ganglia or cortex. The effect of 5-HT on STN neuronal activity involves several 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT2C and 5-HT4 receptors, which have garnered the highest attention on this topic. The multiple regulatory effects exerted by 5-HT are thought to be modified under pathological conditions, altering the activity of the STN, or due to the benefits and side effects of treatments used for Parkinson’s disease, notably the dopamine precursor l-DOPA and high-frequency STN stimulation. Originally understood as a motor center, the STN is also associated with decision making and participates in mood regulation and cognitive performance, two domains of personality that are also regulated by 5-HT. The literature concerning the link between 5-HT and STN is already important, and the functional overlap is evident, but this link is still not entirely understood. The understanding of this link between 5-HT and STN should be increased due to the possible importance of this regulation in the control of fronto-STN loops and inherent motor and non-motor behaviors.The brainstem is a neglected brain area in neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, frontotemporal lobar degeneration and autonomic dysfunction. In Depression, several observations have been made in relation to changes in one particular the Dorsal Raphe Nucleus (DRN) which also points toward as key area in various age-related and neurodevelopmental diseases. The DRN is further thought to be related to stress regulated processes and cognitive events. It is involved in neurodegeneration, e.g., amyloid plaques, neurofibrillary tangles, and impaired synaptic transmission in Alzheimer’s disease as shown in our autopsy findings. The DRN is a phylogenetically old brain area, with projections that reach out to a large number of regions and nuclei of the central nervous system, particularly in the forebrain. These ascending projections contain multiple neurotransmitters. One of the main reasons for the past and current interest in the DRN is its involvement in depression, and its main transmitter serotonin. The DRN also points toward the increased importance and focus of the brainstem as key area in various age-related and neurodevelopmental diseases. This review describes the morphology, ascending projections and the complex neurotransmitter nature of the DRN, stressing its role as a key research target into the neural bases of depression.The pathogenesis of Alzheimer’s disease (AD) is not fully understood. Here we summarize current knowledge on the involvement of the serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid systems in AD, emphasizing the importance of interactions between the serotonergic and the other subcortical modulatory systems during the progression of AD. In physiological conditions, all neurotransmitter systems function in concert and are interdependent at both the neuroanatomical and molecular levels. Through their early involvement in AD, cognitive and behavioral abilities that rely on their interactions also become disrupted. Considering that serotonin (5HT) regulates the release of noradrenaline (NA), dopamine (DA) and acetylcholine (ACh), any alteration in 5HT levels leads to disturbance of NA, DA, and ACh homeostasis in the brain. One of the earliest pathological changes during the prodromal phase of AD is a decrease of serotonergic transmission throughout the brain, with serotonergic receptors being also affected. Additionally, serotonergic and noradrenergic as well as serotonergic and dopaminergic nuclei are reciprocally interconnected. As the serotonergic dorsal raphe nucleus (DRN) is affected by pathological changes early in AD, and the noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental area (VTA) exhibit AD-related pathological changes, their connectivity also becomes altered in AD. Such disrupted interactions among neurotransmitter systems in AD can be used in the development of multi-target drugs. Some of the potential AD therapeutics (such as ASS234, RS67333, tropisetron) target multiple neurotransmitter systems to achieve the best possible improvement of cognitive and behavioral deficits observed in AD. Here, we review how serotonergic system interacts with other subcortical modulatory systems (noradrenergic, dopaminergic, cholinergic, and opioid systems) during AD.Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT2A receptors and inhibitory influences through non-5-HT2A receptors, including 5-HT1A receptors. While the 5-HT2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT2A receptors, activation of a minority of 5-HT2A receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT2A receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field,and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT2A receptors and enhancing activity at mGlu2 receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT2A receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of monoaminergic central pathways such as the serotonergic. link3 The degeneration of serotonergic signaling in striatal and extrastriatal brain regions is an early feature of PD and is associated with several motor and non-motor complications of the disease. Molecular imaging techniques with Positron Emission Tomography (PET) have greatly contributed to the investigation of biological changes in vivo and to the understanding of the extent of serotonergic pathology in patients or individuals at risk for PD. Such discoveries provide with opportunities for the identification of new targets that can be used for the development of novel disease-modifying drugs or symptomatic treatments. Future studies of imaging serotonergic molecular targets will better clarify the importance of serotonergic pathology in PD, including progression of pathology, target-identification for pharmacotherapy, and relevance to endogenous synaptic serotonin levels.