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Current Medicinal Chemistry 2018The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus... (Review)
Review
BACKGROUND
The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases.
OBJECTIVE
This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson's, Huntington's, and Alzheimer's diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.
Topics: Animals; Drug Discovery; Humans; Mental Disorders; Molecular Structure; Neurodegenerative Diseases; Neuroprotective Agents; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
PubMed: 29521210
DOI: 10.2174/0929867325666180309110629 -
Brain Pathology (Zurich, Switzerland) Jul 2017Autism Spectrum Disorder is characterized by sensory anomalies including impaired olfactory identification. Between 5 and 46 percent of individuals with autism have a...
Autism Spectrum Disorder is characterized by sensory anomalies including impaired olfactory identification. Between 5 and 46 percent of individuals with autism have a clinical diagnosis of epilepsy. Primary olfactory cortex (piriform cortex) is central to olfactory identification and is an epileptogenic structure. Cytoarchitectural changes in olfactory cortex may underlie olfactory differences seen in autism. Primary olfactory cortex was sampled from 17 post-mortem autism cases with and without epilepsy, 11 epilepsy cases without autism and 11 typically developed cases. Stereological and neuropathological methods were used to quantify glial, pyramidal and non-pyramidal cell densities in layers of the piriform as well as identify pathological differences in this area and its neighbouring region, the olfactory tubercle. We found increased layer II glial cell densities in autism with and without epilepsy, which were negatively correlated with age and positively correlated with levels of corpora amylacea in layer I. These changes were also associated with greater symptom severity and did not extend to the olfactory tubercle. Glial cell organization may follow an altered trajectory of development with age in autism. The findings are consistent with other studies implicating increased glial cells in the autism brain. Altered cytoarchitecture may contribute to sensory deficits observed in affected individuals. This study provides evidence that autism is linked to alterations in the cytoarchitectural structure that underlies primary sensory processes and is not restricted to heteromodal ("higher") cognitive centers.
Topics: Adolescent; Adult; Age Factors; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Autistic Disorder; Epilepsy; Female; Glial Fibrillary Acidic Protein; Humans; Male; Middle Aged; Neuroglia; Neurons; Olfactory Cortex; Postmortem Changes; Severity of Illness Index; Statistics as Topic; Young Adult
PubMed: 27409070
DOI: 10.1111/bpa.12415 -
Brain Research Oct 2021Depression, rapid eye movement (REM) sleep behavior disorder, and altered olfaction are often present in Parkinson's disease. Our previous studies demonstrated the role...
Depression, rapid eye movement (REM) sleep behavior disorder, and altered olfaction are often present in Parkinson's disease. Our previous studies demonstrated the role of the olfactory bulb (OB) in causing REM sleep disturbances in depression. Furthermore, adenosine A receptors (AR) which are richly expressed in the OB, play an important role in the regulation of REM sleep. Caffeine, an adenosine A receptors and AR antagonist, and other AR antagonists were reported to improve olfactory function and restore age-related olfactory deficits. Therefore, we hypothesized that the AR neurons in the OB may regulate olfaction or odor-guided behaviors in mice. In the present study, we employed chemogenetics to specifically activate or inhibit neuronal activity. Then, buried food test and olfactory habituation/dishabituation test were performed to measure the changes in the mice's olfactory ability. We demonstrated that activation of OB neurons or OB AR neurons shortened the latency of buried food test and enhanced olfactory habituation to the same odors and dishabituation to different odors; inhibition of these neurons showed the opposite effects. Photostimulation of ChR2-expressing OB AR neuron terminals evoked inward current in the olfactory tubercle (OT) and the piriform cortex (Pir), which was blocked by glutamate receptor antagonists 2-amino-5-phosphonopentanoic acid and 6-cyano-7nitroquinoxaline-2,3-dione. Collectively, these results suggest that the OB mediates olfaction via AR neurons in mice. Moreover, the excitatory glutamatergic release from OB neurons to the OT and the Pir were found responsible for the olfaction-mediated effects of OB AR neurons.
Topics: Animals; Male; Mice; Mice, Inbred C57BL; Neurons; Odorants; Olfactory Bulb; Olfactory Cortex; Olfactory Perception; Piriform Cortex; Receptor, Adenosine A2A; Smell
PubMed: 34310936
DOI: 10.1016/j.brainres.2021.147590 -
Synapse (New York, N.Y.) Jul 2023Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs...
Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs (OB) send projections to various CNS regions including the nucleus accumbens (NAcc) and caudate-putamen (CPu). Both the NAcc and CPu receive important dopaminergic input. Emerging evidence suggests that dopamine (DA) is related to anxiety-related behaviors. Therefore, we aimed to investigate the consequences of neonatal olfactory bulbectomy (nOBX) to anxiety-related behavior as assayed in the elevated plus maze (EPM) as well as the expression of dopaminergic receptors (D1-like, D2-like, and D3) in the NAcc and CPu at pre- and post-pubertal ages in the rat. The results show that nOBX increased the number of entries in the open arm of the EPM post-pubertally, suggesting an anxiolytic-related effect. nOBX increased the D2-like binding in the NAcc shell and D3 binding in the NAcc core pre-pubertally. At post-pubertal ages, the D3 binding was reduced at the olfactory tubercle and islands of Calleja in nOBX rats. Alterations in the DA receptor expression may be one mechanism responsible for the observed behavioral modifications in nOBX rats.
Topics: Rats; Animals; Dopamine; Smell; Receptors, Dopamine; Nucleus Accumbens; Anxiety; Anti-Anxiety Agents; Receptors, Dopamine D1
PubMed: 37132073
DOI: 10.1002/syn.22272 -
IBRO Reports Dec 2020The tenia tecta is extensively interconnected with the main olfactory bulb and olfactory cortical areas and is well positioned to contribute to olfactory processing....
The tenia tecta is extensively interconnected with the main olfactory bulb and olfactory cortical areas and is well positioned to contribute to olfactory processing. However, little is known about odor representation within its dorsal (DTT) and ventral (VTT) components. To address this need, spontaneous and odor-evoked activity of DTT and VTT neurons was recorded from urethane anesthetized mice and compared to activity recorded from adjacent areas within adjacent caudomedial aspects of the anterior olfactory nucleus (AON). Neurons recorded from DTT, VTT, and AON exhibited odor-selective alterations in firing rate in response to a diverse set of monomolecular odorants. While DTT and AON neurons exhibited similar tuning breadth, selectivity, and response topography, the proportion of odor-selective neurons was substantially higher in the DTT. These findings provide evidence that the tenia tecta may contribute to the encoding of specific stimulus attributes. Further work is needed to fully characterize functional organization of the tenia tecta and its contribution to sensory representation and utilization.
PubMed: 32793841
DOI: 10.1016/j.ibror.2020.07.010 -
The Journal of Neuroscience : the... May 2020Rodents can successfully learn multiple novel stimulus-response associations after only a few repetitions when the contingencies predict reward. The circuits modified...
Rodents can successfully learn multiple novel stimulus-response associations after only a few repetitions when the contingencies predict reward. The circuits modified during such reinforcement learning to support decision-making are not known, but the olfactory tubercle (OT) and posterior piriform cortex (pPC) are candidates for decoding reward category from olfactory sensory input and relaying this information to cognitive and motor areas. Through single-cell recordings in behaving male and female C57BL/6 mice, we show here that an explicit representation for reward category emerges in the OT within minutes of learning a novel odor-reward association, whereas the pPC lacks an explicit representation even after weeks of overtraining. The explicit reward category representation in OT is visible in the first sniff (50-100 ms) of an odor on each trial, and precedes the motor action. Together, these results suggest that the coding of stimulus information required for reward prediction does not occur within olfactory cortex, but rather in circuits involving the olfactory striatum. Rodents are olfactory specialists and can use odors to learn contingencies quickly and well. We have found that mice can readily learn to place multiple odors into rewarded and unrewarded categories. Once they have learned the rule, they can do such categorization in a matter of minutes (<10 trials). We found that neural activity in olfactory cortex largely reflects sensory coding, with very little explicit information about categories. By contrast, neural activity in a brain region in the ventral striatum is rapidly modified in a matter of minutes to reflect reward category. Our experiments set up a paradigm for studying rapid sensorimotor reinforcement in a circuit that is right at the interface of sensory input and reward areas.
Topics: Animals; Female; Male; Mice; Mice, Inbred C57BL; Neurons; Olfactory Perception; Olfactory Tubercle; Piriform Cortex; Reward
PubMed: 32321744
DOI: 10.1523/JNEUROSCI.2604-19.2020 -
Journal of Chemical Neuroanatomy Jul 2018Smad proteins are known to transduce the action of TGF-β superfamily proteins including TGF-βs, activins, and bone morphogenetic proteins (BMPs). In this study, we...
Smad proteins are known to transduce the action of TGF-β superfamily proteins including TGF-βs, activins, and bone morphogenetic proteins (BMPs). In this study, we examined the expression of Smad1, -2, -3, -4, -5, and -8 mRNA in the rat brain by means of RT-PCR and in situ hybridization (ISH). In addition, we examined the nuclear accumulation of Smad1, -2, -3, -5, and -8 proteins after intracerebroventricular injection of TGF-β1, activin A, or BMP6 with immunohistochemistry to investigate whether TGF-β, activin, and/or BMP activate Smads in the rat brain. RT-PCR analysis revealed that Smad1, -2, -3, -4, -5, and -8 mRNA was expressed in the brain and that the Smad3 and Smad8 mRNA differed in the expression level between brain regions. For example, there were high levels of expression of Smad3 mRNA in the cerebral cortex, caudate putamen/globus pallidus, and cerebellum, but low levels in the thalamus and midbrain. Expression of Smad8 mRNA was higher in the midbrain, cerebellum, and pons/medulla oblongata in comparison to the olfactory bulb, cerebral cortex, caudate putamen/globus pallidus, hippocampus/dentate gyrus, and thalamus. ISH signals for Smad1 mRNA were widely detected in the brain except for a small number of regions including the olfactory tubercle, posterior region of hypothalamus, and cerebellar nuclei. ISH signals for Smad2 mRNA were abundantly observed in several brain regions including the olfactory bulb, piriform cortex, basal ganglia, cingulate cortex, epithalamus, including the pineal gland and medial habenular nuclei, hypothalamus, inferior colliculi of the midbrain, and some nuclei in the pons, cerebellar cortex, and choroid plexus. ISH signals for Smad3 mRNA were also abundantly observed in several brain regions. Especially strong signals for Smad3 mRNA were observed in the olfactory tubercle, piriform cortex, basal ganglia, dentate gyrus, and cingulate cortex. ISH signals for Smad5 and Smad8 mRNA were restricted to a small number of brain regions, the signal intensity of which was weak. ISH signals for Smad4 mRNA were detected in all regions examined. Intracerebroventricular injection of activin A induced nuclear accumulation of Smad2 and Smad3 immunoreactivity in neurons. In contrast, intracerebroventricular injection of TGF-β1 or BMP6 did not induce nuclear accumulation of the immunoreactivity for any Smad in neurons. These results suggest that activin-Smad signaling plays an important role in brain homeostasis.
Topics: Animals; Brain; Male; RNA, Messenger; Rats; Rats, Sprague-Dawley; Smad Proteins
PubMed: 29196107
DOI: 10.1016/j.jchemneu.2017.11.012 -
Progress in Neurobiology Jun 2021During mammalian evolution, primate neocortex expanded, shifting hippocampal functional networks away from primary sensory cortices, towards association cortices....
During mammalian evolution, primate neocortex expanded, shifting hippocampal functional networks away from primary sensory cortices, towards association cortices. Reflecting this rerouting, human resting hippocampal functional networks preferentially include higher association cortices, while those in rodents retained primary sensory cortices. Research on human visual, auditory and somatosensory systems shows evidence of this rerouting. Olfaction, however, is unique among sensory systems in its relative structural conservation throughout mammalian evolution, and it is unknown whether human primary olfactory cortex was subject to the same rerouting. We combined functional neuroimaging and intracranial electrophysiology to directly compare hippocampal functional networks across human sensory systems. We show that human primary olfactory cortex-including the anterior olfactory nucleus, olfactory tubercle and piriform cortex-has stronger functional connectivity with hippocampal networks at rest, compared to other sensory systems. This suggests that unlike other sensory systems, olfactory-hippocampal connectivity may have been retained in mammalian evolution. We further show that olfactory-hippocampal connectivity oscillates with nasal breathing. Our findings suggest olfaction might provide insight into how memory and cognition depend on hippocampal interactions.
Topics: Brain Mapping; Cerebral Cortex; Hippocampus; Humans; Olfactory Cortex; Sense Organs; Smell
PubMed: 33640412
DOI: 10.1016/j.pneurobio.2021.102027 -
BioRxiv : the Preprint Server For... Dec 2023The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Though we have identified...
The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Though we have identified many brain nuclei that play various roles in reward processing, a significant gap remains in understanding how valence encoding transforms through the layers of sensory processing. To address this gap, we carried out a comparative investigation of the olfactory tubercle (OT), and the ventral pallidum (VP) - 2 connected nuclei of the basal ganglia which have both been implicated in reward processing. First, using anterograde and retrograde tracing, we show that both D1 and D2 neurons of the OT project primarily to the VP and minimally elsewhere. Using 2-photon calcium imaging, we then investigated how the identity of the odor and reward contingency of the odor are differently encoded by neurons in either structure during a classical conditioning paradigm. We find that VP neurons robustly encode reward contingency, but not identity, in low-dimensional space. In contrast, OT neurons primarily encode odor identity in high-dimensional space. Though D1 OT neurons showed larger response vectors to rewarded odors than other odors, we propose this is better interpreted as identity encoding with enhanced contrast rather than as valence encoding. Finally, using a novel conditioning paradigm that decouples reward contingency and licking vigor, we show that both features are encoded by non-overlapping VP neurons. These results provide a novel framework for the striatopallidal circuit in which a high-dimensional encoding of stimulus identity is collapsed onto a low-dimensional encoding of motivational valence.
PubMed: 37577586
DOI: 10.1101/2023.08.01.551547 -
Current Biology : CB Apr 2021Pleasant odorants are represented in the posterior olfactory bulb (pOB) in mice. How does this hedonic information generate odor-motivated behaviors? Using optogenetics,...
Pleasant odorants are represented in the posterior olfactory bulb (pOB) in mice. How does this hedonic information generate odor-motivated behaviors? Using optogenetics, we report here that stimulating the representation of pleasant odorants in a sensory structure, the pOB, can be rewarding, self-motivating, and is accompanied by ventral tegmental area activation. To explore the underlying neural circuitry downstream of the olfactory bulb (OB), we use 3D high-resolution imaging and optogenetics and determine that the pOB preferentially projects to the olfactory tubercle, whose increased activity is related to odorant attraction. We further show that attractive odorants act as reinforcers in dopamine-dependent place preference learning. Finally, we extend those findings to humans, who exhibit place preference learning and an increase BOLD signal in the olfactory tubercle in response to attractive odorants. Thus, strong and persistent attraction induced by some odorants is due to a direct gateway from the pOB to the reward system.
Topics: Animals; Emotions; Male; Mice; Mice, Inbred C57BL; Motivation; Odorants; Olfactory Bulb; Olfactory Perception; Optogenetics; Reward; Smell
PubMed: 33607032
DOI: 10.1016/j.cub.2021.01.066