Dysfunction of Fronto-Subcortical Circuitry in Fronto-Temporal Dementia

In the last years, some studies have shown that behavior disorder seems in frontotemporal dementia is related to dysfunction in the fronto-subcortical circuitry. Objectives: We did a narrative literature review concerning fron-to-subcortical circuitry and frontotemporal dementia (FTD). Methods: Ma-nuscripts related to fronto-subcortical network and frontotemporal dementia were selected for further analysis. Results: From the executions of simple motor actions to the most complex behaviors like goal-direct behavior and social cognition, the fronto-subcortical circuitry involves an intrigued network of fibers that reaches to basal ganglia nuclei. Recently, researchers have shown five parallel fronto-subcortical circuits integrating and segregating information from the frontal cortex to basal ganglia. Understanding the relationship between the fronto-subcortical circuit dysfunctions and neurodegenerative diseases requires studying the functional anatomy and neurochemical basis involved. Conclusions: In this view, it is essential to review the functional anatomy of the fronto-subcortical network, and it’s correlated with clinical aspects to pursuing a better therapeutic approach.


Introduction
An enormous explosion of life diversity occurred in the Cambrian era; vertebrates like fish, amphibians, reptiles, birds, and mammals developed a vertebrate skeleton, which allowed them to have more fast movement. This highly sophis-modulate drive behavior, motivation, and executive function to better organize strategy, motor planning, and execution for adequate decision-making [16]- [22]. Three parallel segregated circuits reach the dorsal and ventral striatum, Globus pallidus, substantia nigra and thalamus, and modulate motivation, reward, and emotions response [16] [17] [18] [20] [21] [23] [24]. The dorsolateral prefrontal (DLPFC) and associate parietal cortex (APC) will modulate the executive functions while the anterior cingulate cortex (ACC) will participating on the motivation and reward system and, finally the orbitofrontal lateral cortex will modulate the behavior inhibitory control (Figure 1).

The Frontostriatal Connectivity and Synaptic Plasticity
The striatum is the main input structure of basal ganglia formed for three major sources from the cerebral cortex, thalamus, and brainstem [16] [19] [26] [27] [28]. As the basal ganglia's primary input nucleus, the striatum will participate to receive, integrate, or segregate from other incoming signals and relayed to appropriate outputs [29]. The striatum also can be subdivided into the dorsal and ventral striatum. The dorsal striatum nucleus is dividing into the dorsomedial (DMS) and dorsolateral (DLS) regions, receiving projections from the frontal and parietal-associated cortex and sensorimotor cortex. On the other hand, the ventral striatum/nuclei Accumbens (NAc) receives projections from limbic structures, including the amygdala, hippocampus, medial prefrontal cortex, and anterior cingulate cortex [16] [26] [29] [30] [31]. This basal nucleus also receives indirect cortical input through the intralaminar thalamic nuclei, especially the centromedian-parafascicular nuclei (CM-pf). The striatum contains several cell types that are generally divided into two general groups: projection neurons and interneurons [16] [32] [33]. Most cells are GABAergic neurons, including a large population of medium spiny neurons (MSNs) and interneurons. Furthermore, it's essential to address a lack of striatal glutamatergic neurons, although many cortical glutamatergic neurons are projecting to the striatum [16] [24]. The GABAergic's striatal interneurons can be divided into at least two classes, based on their physiological properties: 1) fastspiking (FS-parvalbumin-positive cells) and 2) Low-threshold spiking (somatostatin-oxide-synthase, and neuropeptide-Y-positive cells (NPY); also potentially calretinin-positive interneurons) [32] [34]. Although interneurons constitute a tiny population of the dorsal striatum compared to that of MSNs, the minority exerts powerful inhibitory effects on MSNs through GABAergic transmission. There is also a dense innervation of mesencephalic dopaminergic axons that reaches the striatum and the presence of cholinergic interneurons [35].
Besides the GABAergic interneurons, there are two classes of striatal dopaminergic receptors: D1-like (D1 and D5 receptors) and D2-like (D2, D3, and D4 receptors). All dopaminergic receptors are coupled with G-protein receptors. However, D1 receptors will activate Gs proteins, while D2 stimulates inhibitory Gi proteins [35]. The D1 receptor (D1R) stimulates the adenylciclase and presenting a phasic response to dopamine. On the other hand, the D2 receptor will respond in the tonic way to inhibit the neurons' activity through the Gi-coupled signaling pathway [20] [26] [36].
It is also essential to address that the substantia nigra compacta (SNc), which project dopaminergic neurons to the striatum, will form clusters called cell islands [16]. These cell islands are histochemically organized in two compartments: 1) striossomes, and 2) matrix. Striossomes occupy 10% -15% of striatal volume and are rich in substance P (SP), which acts increasing DA release and has a vital role in the direct pathway, which express MSNs D1R. The matrix, by contrast, is enriched with enkephalin (ENK), D2-receptor (D2R), and acetylcholine and cholinergic markers, including acetylcholine esterase (AChE) and choline acetyltransferase (ChAT) and have an essential role in the indirect pathway [29].
In summary, once the glutamatergic inputs from the sensorimotor cortex reach the striatum and activate the direct-pathway, MSNs D1 receptors will project directly to GABAergic neurons in the GPi and SNr, activating these neurons, which in turn sending axons to motor nuclei of the thalamus, become inhibited [35]. This information flow's net effect, which promote a disinhibition of excitatory thalamocortical projections [16] [40].
Furthermore, the indirect pathway also receives glutamatergic inputs from the cortex. The glutamatergic input onto GABAergic MSNs D2 receptors inhibits GABAergic pallidal neurons of the GPe. In this case, the target of the GPe neurons, the glutamatergic neurons of the subthalamic nuclei (STN), are disinhibited [35]. Finally, the disinhibition of STN glutamatergic neurons could activate inhibitory output neurons of the GPi and SNr, resulting in an inhibition of excitatory thalamocortical projection neurons promoting a reduction of excitatory projections from the thalamus to the cortex, inhibiting the motor movement [35].
Another mesencephalic area crucial in the fronto-subcortical circuits is the ventral tegmental area (VTA). Projections from VTA can be classified as mesolimbic and mesocortical. An essential mesolimbic projection of the VTA is the nucleus Accumbens (NAc), olfactory tubercle, amygdala, and septum. The mesocortical pathway reach the prefrontal, cingulate, and perirhinal cortex [41] [42] besides locus ceruleus and other cortical areas. One of the most critical roles of the mesocorticolimbic pathway is to work in goal-direct behavior, drug induced-reward, selective attention, and working memory [43].

Others Neurotransmitters Systems Influencing Fronto-Subcortical Circuits
One of the most important neurotransmitters of the mammalian brain is the norepinephrine (NE). These neurotransmitters modulated attention, arousal, and cognition during many behaviors and works associated with dopamine (DA). It's shown that noradrenergic neurons from the locus ceruleus project to the entire cortex and hippocampus, cerebellum, and spinal cord. In the cerebral cortex, B1 receptors receive noradrenergic neurons and works associated with DA to promote a better signal-to-noise ratio of the atentional system. Studies showed that blocking NE transporters leads to an increase in DA and NE levels in the prefrontal cortex [44]. These findings suggest that the DA action in the frontal cortex is modulating by NE transporters [44] [45] [46]. Furthermore, there is a prominent innervation of serotonin neurons and an essential expression of 5HT receptors distributed in the prefrontal cortex modulating part of the cortical function [43] [47] [48]. Some 5HT receptors can cause frontal inhibition on the DA neurons [48] [49]. For instance, 5HT2c and 5HT2a decrease DA in the frontal cortex and striatum, while the 5HT3, 5HT1a, and 5HT1b increase the release of DA in the frontal cortex, striatum, amygdala and hippocampus [48] [50].
One of the essential neurochemical modulation related to a balance of behavior control is the interaction between the DA and 5HT receptors (5HT/DA interactions) both in the basal ganglia and frontal cortex [43] [51]. The cell bodies and terminal regions of all three DA pathways (SNc, mesolimbic and mesocortical) are innervated by 5-HT neurons originating in the medial and dorsal raphe nuclei [43]

Clinical Aspects of the Fronto-Subcortical Behavioral Syndromes
One of the most relevant clinical aspects of frontotemporal dementia is a beha-  (Figure 3).
The dysexecutive syndrome is characterized by dysfunction in the system that regulates the executive plans and monitors errors to adjust task performance [18]. Patients with dysexecutive-FTD have difficulty maintaining attention, shifting sets to control the mistakes in response to changing task demands, and selecting goals for a better decision making related to social contingencies [18].
Also, there are associated features like reduced verbal and design fluency, impairment of memory search strategies on learning, and motor programming disturbances [25]. This dysexecutive syndrome also can see in other neuropsychiatric disorders like Parkinson's disease, Attention Deficit Disorders, Depression, etc. [18].

The Anterior Cingulate Prefrontal Syndrome
The anterior cingulate cortex (ACC) has two subdivisions: 1) the dorsal cogni-  thalamus nuclei. The thalamic nuclei, especially the mediodorsal and ventral anterior portion, and the intralaminar nuclei will close the looping sending projections back to the dorsal division of ACC turn, succeeding projection to DLPC [27] [61]. This integrated network links the dorsal ACC with the dorsolateral cortex. It will be responsible for modulating executive or attention functions, especially motivational behavior, complex motor control, error detection, anticipating cognitive task, and working memory [25] [61] (Figure 4).
The VS sends projections to innervate the rostromedial GPi and ventral Pallidum (VP) and the rostrodorsal STN [63]. There may also be a less well-defined indirect loop projecting from ventral striatum to the rostral pole of the GPe [64].
The external pallidum, in turn, connects to the medial STN, which returns projections to the ventral pallidum [65] and, then to the mediodorsal thalamus [66].
Finally, the looping is closed when the mediodorsal thalamus sends the final projection back to the limbic cortex, reaching the rostromedial portion [24] ( Figure 5). It is essential to address that the ventral subdivision of ACC comprises the subgenual cingulate division (ACCsg) (BA 32), which predominantly connects with the amygdala, medial orbitofrontal cortex, anterior insula, medial temporal lobe, hypothalamus, periaqueductal grey and dorsal brainstem [13] [61] [67]. This circuit is related to salience monitoring of emotional and motiva-

The Orbitofrontal Syndrome
The orbitofrontal cortex also shows projections towards the basal ganglia. Brodmann's area 11 corresponds to the orbitofrontal circuit, and BA 10 and 47 corresponds to the medial part of the frontal gyrus. Both will send projections to the basal ganglia, especially the ventromedial part of the caudate nuclei. This area also receives projections from the visual cortex, auditory association cortex, and upper and lower temporal gyrus [17] [18] [23] [58]. The ventromedial caudate nuclei, in turn, send GABAergic projections to the medial segment of GPi, which is located medially to the dorsolateral caudate nuclei and the rostromedial portion of the SNr [17]. The GPi, in turn, sends GABAergic projections straightforward to the ventral-anterior and dorsomedial thalamic nucleus [17] [58] [71]. The thalamic nucleus will send back glutamatergic projections to the lateral orbitofrontal cortex, closing the direct inhibitory circuit [18] [58] [71]. There is also an indirect pathway that project GABAergic neurons out of the ventromedial nuclei to the GPe, which will send GABAergic projections to the lateral subthalamic nuclei (LSTN). The LSTN, in turn, sends glutamatergic projections to GPi and SNr. The GPi and SNr neurons will project onto the thalamus in the medial magnocellular part of the ventral-anterior nucleus. In the magnocellular inferomedial portion of the mediodorsal thalamus, closing the OLPFC inhibitory circuit ( Figure 6) [58].
The orbitofrontal circuit provides an essential role in the control of emotional behavior. Thus, lesions in this area disconnect the frontal monitoring system Open Journal of Psychiatry from limbic input control (70). Another significant dysfunction of OFC syndrome is impulsive and disinhibition disorder, which affects their social life in different ways where patients have a lack of judgment and social clues, inappropriate sexual remarks, antisocial behavior as irritability, emotional lability, mania or hypomania, abnormal motor behavior [

Final Considerations
In the last years, some researches have shown the link between fronto-subcortical circuits dysfunction and neuropsychiatric disease. The fronto-subcortical circuit dysfunction can be treated with some drugs that acting modulating neurotransmitters in this pathway. It's imperative to consider that understanding the functional anatomy and neurochemical modulation related to this network is the best way to choose drugs based on the comprehension of their action in the fronto-subcortical pathway. For instance, to understand to balance between serotonin receptors and dopamine release in the frontal lobe, or the effect of NE receptors in the Dopa release on the frontal lobe, as well as, the importance of mesocortical, mesolimbic and mesostriatal dopamine pathway will contribute to choose a better therapeutic approach in front of the challenge, which is to control some behavioral disorders seems in the behavioral variant of frontotemporal dementia (bv-FTD).

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper. Open Journal of Psychiatry