Sources of Rapid and Delayed New Lower Jaw Input in the Forepaw Barrel Subfield (FBS) in Rat Primary Somatosensory Cortex (SI) Following Forelimb Deafferentation.

Previously, we reported an immediate emergence of new lower jaw input to the anterior forepaw barrel subfield (FBS) in primary somatosensory cortex (SI) following forelimb deafferentation. However, a delay of 7 weeks or more post-amputation results in the presence of this new input to both anterior and posterior FBS. The immediate change suggests pre-existing latent lower jaw input in the FBS, whereas the delayed alteration implies the involvement of alternative sources. One possible source for immediate lower jaw responses is the neighboring lower jaw barrel subfield (LJBSF). We used anatomical tracers to investigate the possible projection of LJBSF to the FBS in normal and forelimb-amputated rats. Our findings are as follows: (1) anterograde tracer injection into LJBSF in normal and amputated rats labeled fibers and terminals exclusively in the anterior FBS; (2) retrograde tracer injection in the anterior FBS in normal and forelimb-amputated rats, heavily labeled cell bodies predominantly in the posterior LJBSF, with fewer in the anterior LJBSF; (3) retrograde tracer injection in the posterior FBS in normal and forelimb-amputated rats, sparsely labeled cell bodies in the posterior LJBSF; (4) retrograde tracer injection in anterior and posterior FBS in normal and forelimb-amputated rats, labeled cells exclusively in ventral posterior lateral (VPL) nucleus and posterior thalamus (PO); (5) retrograde tracer injection in LJBSF-labeled cell bodies exclusively in ventral posterior medial thalamic nucleus and PO. These findings suggest that LJBSF facilitates rapid lower jaw reorganization in the anterior FBS, whereas VPL and/or other subcortical sites provide a likely substrate for delayed reorganization observed in the posterior FBS.

Quantitative metrics commonly derived from diffusion tractography covary with streamline length: a characterization and method of adjustment.

Tractography algorithms are used extensively to delineate white matter structures, by operating on the voxel-wise information generated through the application of diffusion tensor imaging (DTI) or other models to diffusion weighted (DW) magnetic resonance imaging (MRI) data. Through statistical modelling, we demonstrate that these methods commonly yield substantial and systematic associations between streamline length and several tractography derived quantitative metrics, such as fractional anisotropy (FA). These associations may be described as piecewise linear. For streamlines shorter than an inflection point (determined for a group of tracts delineated for each individual brain), estimates of FA exhibit a positive linear relation with streamline length. For streamlines longer than the point of inflection, the association is weaker, with the slope of the relationship between streamline length and FA differing only marginally from zero. As the association is most pronounced for a range of streamline lengths encountered typically in DW imaging of the human brain (less than ~ 100 mm), our results suggest that some quantitative metrics derived from diffusion tractography have the potential to mislead, if variations in streamline length are not considered. A method is described, whereby an Akaike information weighted average of linear, Blackman and piecewise linear model predictions, may be used to compensate effectively for the association of FA (and other quantitative metrics) with streamline length, across the entire range of streamline lengths present in each specimen.

Cross-species striatal hubs: Linking anatomy to resting-state connectivity.

Corticostriatal connections are essential for motivation, cognition, and behavioral flexibility. There is broad interest in using resting-state functional magnetic resonance imaging (rs-fMRI) to link circuit dysfunction in these connections with neuropsychiatric disorders. In this paper, we used tract-tracing data from non-human primates (NHPs) to assess the likelihood of monosynaptic connections being represented in rs-fMRI data of NHPs and humans. We also demonstrated that existing hub locations in the anatomical data can be identified in the rs-fMRI data from both species. To characterize this in detail, we mapped the complete striatal projection zones from 27 tract-tracer injections located in the orbitofrontal cortex (OFC), dorsal anterior cingulate cortex (dACC), ventromedial prefrontal cortex (vmPFC), ventrolateral PFC (vlPFC), and dorsal PFC (dPFC) of macaque monkeys. Rs-fMRI seeds at the same regions of NHP and homologous regions of human brains showed connectivity maps in the striatum mostly consistent with those observed in the tracer data. We then examined the location of overlap in striatal projection zones. The medial rostral dorsal caudate connected with all five frontocortical regions evaluated in this study in both modalities (tract-tracing and rs-fMRI) and species (NHP and human). Other locations in the caudate also presented an overlap of four frontocortical regions, suggesting the existence of different locations with lower levels of input diversity. Small retrograde tracer injections and rs-fMRI seeds in the striatum confirmed these cortical input patterns. This study sets the ground for future studies evaluating rs-fMRI in clinical samples to measure anatomical corticostriatal circuit dysfunction and identify connectional hubs to provide more specific treatment targets for neurological and psychiatric disorders.

Adaptation of the layer V supraspinal motor corticofugal projections from the primary (M1) and premotor (PM) cortices after CNS motor disorders in non-human primates: A survey.

Motor commands are transmitted from the motor cortical areas to effectors mostly via the corticospinal (CS) projection. Several subcortical motor nuclei also play an important role in motor control, the subthalamic nucleus, the red nucleus, the reticular nucleus and the superior colliculus. These nuclei are influenced by motor cortical areas via respective corticofugal projections, which undergo complex adaptations after motor trauma (spinal cord/motor cortex injury) or motor disease (Parkinson), both in the absence or presence of putative treatments, as observed in adult macaque monkeys. A dominant effect was a nearly complete suppression of the corticorubral projection density and a strong downregulation of the corticoreticular projection density, with the noticeable exception in the latter case of a considerable increase of projection density following spinal cord injury, even enhanced when an anti-NogoA antibody treatment was administered. The effects were diverse and less prominent on the corticotectal and corticosubthalamic projections. The CS projection may still be the major efferent pathway through which motor adaptations can take place after motor trauma or disease. However, the parallel supraspinal motor corticofugal projections may also participate in connectional adaptations supporting the functional recovery of motor abilities, representing potential targets for future clinical strategies, such as selective electrical neurostimulations.

Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

Input and Output Connections of the Crow Nidopallium Caudolaterale.

The avian telencephalic structure nidopallium caudolaterale (NCL) functions as an analog to the mammalian prefrontal cortex. In crows, corvid songbirds, it plays a crucial role in higher cognitive and executive functions. These functions rely on the NCL's extensive telencephalic connections. However, systematic investigations into the brain-wide connectivity of the NCL in crows or other songbirds are lacking. Here, we studied its input and output connections by injecting retrograde and anterograde tracers into the carrion crow NCL. Our results, mapped onto a published carrion crow brain atlas, confirm NCL multisensory connections and extend prior pigeon findings by identifying a novel input from the hippocampal formation. Furthermore, we analyze crow NCL efferent projections to the arcopallium and report newly identified arcopallial neurons projecting bilaterally to the NCL. These findings help to clarify the role of the NCL as central executive hub in the corvid songbird brain.

Ischemia-reperfusion myocardial infarction induces remodeling of left cardiac-projecting stellate ganglia neurons.

Neurons in the stellate ganglion (SG) provide sympathetic innervation to the heart, brown adipose tissue (BAT), and other organs. Sympathetic innervation to the heart becomes hyperactive following myocardial infarction (MI). The impact of MI on the morphology of cardiac sympathetic neurons is not known, but we hypothesized that MI would stimulate increased cell and dendritic tree size in cardiac neurons. In this study, we examined the effects of ischemia-reperfusion MI on sympathetic neurons using dual retrograde tracing methods to allow detailed characterization of cardiac- and BAT-projecting neurons. Different fluorescently conjugated cholera toxin subunit B (CTb) tracers were injected into the pericardium and the interscapular BAT pads, respectively. Experimental animals received a 45-min occlusion of the left anterior descending coronary artery and controls received sham surgery. One week later, hearts were collected for assessment of MI infarct and SGs were collected for morphological or electrophysiological analysis. Cardiac-projecting SG neurons from MI mice had smaller cell bodies and shorter dendritic trees compared with sham animals, specifically on the left side ipsilateral to the MI. BAT-projecting neurons were not altered by MI, demonstrating the subpopulation specificity of the response. The normal size and distribution differences between BAT- and cardiac-projecting stellate ganglion neurons were not altered by MI. Patch-clamp recordings from cardiac-projecting left SG neurons revealed increased spontaneous excitatory postsynaptic currents despite the decrease in cell and dendritic tree size. Thus, increased dendritic tree size does not contribute to the enhanced sympathetic neural activity seen after MI.NEW & NOTEWORTHY Myocardial infarction (MI) causes structural and functional changes specifically in stellate ganglion neurons that project to the heart, but not in cells that project to brown adipose fat tissue.

Analyzing Thalamocortical Tract-Tracing Experiments in a Common Reference Space.

Current mesoscale connectivity atlases provide limited information about the organization of thalamocortical projections in the mouse brain. Labeling the projections of spatially restricted neuron populations in thalamus can provide a functionally relevant level of connectomic analysis, but these need to be integrated within the same common reference space. Here, we present a pipeline for the segmentation, registration, integration and analysis of multiple tract-tracing experiments. The key difference with other workflows is that the data is transformed to fit the reference template. As a test-case, we investigated the axonal projections and intranuclear arrangement of seven neuronal populations of the ventral posteromedial nucleus of the thalamus (VPM), which we labeled with an anterograde tracer. Their soma positions corresponded, from dorsal to ventral, to cortical representations of the whiskers, nose and mouth. They strongly targeted layer 4, with the majority exclusively targeting one cortical area and the ones in ventrolateral VPM branching to multiple somatosensory areas. We found that our experiments were more topographically precise than similar experiments from the Allen Institute and projections to the primary somatosensory area were in agreement with single-neuron morphological reconstructions from publicly available databases. This pilot study sets the basis for a shared virtual connectivity atlas that could be enriched with additional data for studying the topographical organization of different thalamic nuclei. The pipeline is accessible with only minimal programming skills via a Jupyter Notebook, and offers multiple visualization tools such as cortical flatmaps, subcortical plots and 3D renderings and can be used with custom anatomical delineations.

Cytoarchitectonic and connection stripes in the dysgranular insular cortex in the macaque monkey.

The insula has been classically divided into broad granular, dysgranular, and agranular architectonic sectors. We previously proposed a novel partition, dividing each sector into four to seven sharply delimited architectonic areas, with the dysgranular areas being possibly further subdivided into subtle horizontal partitions or "stripes." In architectonics, discrete subparcellations are prone to subjective variability and need being supported with additional neuroanatomical methods. Here, using a secondary analysis of indirect connectional data in the rhesus macaque monkey, we examined the spatial relationship between the dysgranular architectonic stripes and tract-tracing labeling patterns produced in the insula with injections of neuronal tracers in other cortical regions. The injections consistently produced sharply delimited patches of anterograde and/or retrograde labeling, which formed stripes across consecutive coronal sections of the insula. While the overall pattern of labeling on individual coronal sections varied with the injection site, the boundaries of the patches consistently coincided with architectonic boundaries on an adjacent cyto- (Nissl) and/or myelo- (Gallyas) architectonic section. This overlap supports the existence of a fine dysgranular stripe-like partition of the primate insula, with possibly major implications for interoceptive processing in primates including humans. The modular organization of the insula could underlie a serial stream of integration from a dorsal primary interoceptive cortex toward progressively more ventral egocentric "self-agency" and allocentric "social" dysgranular processing units.

Single basolateral amygdala neurons in macaques exhibit distinct connectional motifs with frontal cortex.

Basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for appropriate emotional responding and decision making. While it is appreciated that single BLA neurons branch and project to multiple areas in frontal cortex, the organization and frequency of this branching has yet to be fully characterized. Here, we determined the projection patterns of more than 3,000 macaque BLA neurons. We found that one-third of BLA neurons had two or more distinct projection targets in frontal cortex and subcortical structures. The patterns of single BLA neuron projections to multiple areas were organized into repeating motifs that targeted distinct sets of areas in medial and ventral frontal cortex, indicative of separable BLA networks. Our findings begin to reveal the rich structure of single-neuron connections in the non-human primate brain, providing a neuroanatomical basis for the role of BLA in coordinating brain-wide responses to valent stimuli.

Cerebellar Nuclei Receiving Orofacial Proprioceptive Signals through the Mossy Fiber Pathway from the Supratrigeminal Nucleus in Rats.

Proprioception from muscle spindles is necessary for motor function executed by the cerebellum. In particular, cerebellar nuclear neurons that receive proprioceptive signals and send projections to the lower brainstem or spinal cord play key roles in motor control. However, little is known about which cerebellar nuclear regions receive orofacial proprioception. Here, we investigated projections to the cerebellar nuclei from the supratrigeminal nucleus (Su5), which conveys the orofacial proprioception arising from jaw-closing muscle spindles (JCMSs). Injections of an anterograde tracer into the Su5 resulted in a large number of labeled axon terminals bilaterally in the dorsolateral hump (IntDL) of the cerebellar interposed nucleus (Int) and the dorsolateral protuberance (MedDL) of the cerebellar medial nucleus. In addition, a moderate number of axon terminals were ipsilaterally labeled in the vestibular group Y nucleus (group Y). We electrophysiologically detected JCMS proprioceptive signals in the IntDL and MedDL. Retrograde tracing analysis confirmed bilateral projections from the Su5 to the IntDL and MedDL. Furthermore, anterograde tracer injections into the external cuneate nucleus (ECu), which receives other proprioceptive input from forelimb/neck muscles, resulted in only a limited number of ipsilaterally labeled terminals, mainly in the dorsomedial crest of the Int and the group Y. Taken together, the Su5 and ECu axons almost separately terminated in the cerebellar nuclei (except for partial overlap in the group Y). These data suggest that orofacial proprioception is differently processed in the cerebellar circuits in comparison to other body-part proprioception, thus contributing to the executive function of orofacial motor control.

Caudal DMN neurons innervate the spleen and release CART peptide to regulate neuroimmune function.

BACKGROUND: Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve, which primarily originates from the dorsal motor nucleus (DMN), plays an important role in rapidly dampening inflammation by regulating splenic function. However, direct vagal innervation of the spleen, which houses the majority of immune and inflammatory cells, has not been established. As an alternative to direct innervation, an anti-inflammatory reflex pathway has been proposed which involves the vagus nerve, the sympathetic celiac ganglion, and the neurotransmitter norepinephrine. Although sympathetic regulation of inflammation has been shown, the interaction of the vagus nerve and the celiac ganglia requires a unique interaction of parasympathetic and sympathetic inputs, making this putative mechanism of brain-spleen interaction controversial. BODY: As neuropeptides can be expressed at relatively high levels in neurons, we reasoned that DMN neuropeptide immunoreactivity could be used to determine their target innervation. Employing immunohistochemistry, subdiaphragmatic vagotomy, viral tract tracing, CRISPR-mediated knock-down, and functional assays, we show that cocaine and amphetamine-regulated transcript (CART) peptide-expressing projection neurons in the caudal DMN directly innervate the spleen. In response to lipopolysaccharide (LPS) stimulation, CART acts to reduce inflammation, an effect that can be augmented by intrasplenic administration of a synthetic CART peptide. These in vivo effects could be recapitulated in cultured splenocytes, suggesting that these cells express the as yet unidentified CART receptor(s). CONCLUSION: Our results provide evidence for direct connections between the caudal DMN and spleen. In addition to acetylcholine, these neurons express the neuropeptide CART that, once released, acts to suppress inflammation by acting directly upon splenocytes.

Machine Learning-assisted Quantitative Mapping of Intracortical Axonal Plasticity Following a Focal Cortical Stroke in Rodents.

Stroke destroys neurons and their connections leading to focal neurological deficits. Although limited, many patients exhibit a certain degree of spontaneous functional recovery. Structural remodeling of the intracortical axonal connections is implicated in the reorganization of cortical motor representation maps, which is considered to be an underlying mechanism of the improvement in motor function. Therefore, an accurate assessment of intracortical axonal plasticity would be necessary to develop strategies to facilitate functional recovery following a stroke. The present study developed a machine learning-assisted image analysis tool based on multi-voxel pattern analysis in fMRI imaging. Intracortical axons originating from the rostral forelimb area (RFA) were anterogradely traced using biotinylated dextran amine (BDA) following a photothrombotic stroke in the mouse motor cortex. BDA-traced axons were visualized in tangentially sectioned cortical tissues, digitally marked, and converted to pixelated axon density maps. Application of the machine learning algorithm enabled sensitive comparison of the quantitative differences and the precise spatial mapping of the post-stroke axonal reorganization even in the regions with dense axonal projections. Using this method, we observed a substantial extent of the axonal sprouting from the RFA to the premotor cortex and the peri-infarct region caudal to the RFA. Therefore, the machine learningassisted quantitative axonal mapping developed in this study can be utilized to discover intracortical axonal plasticity that may mediate functional restoration following stroke.

Central projections of auditory nerve fibers in the western rat snake (Pantherophis obsoletus).

Despite the absence of tympanic middle ears, snakes can hear. They are thought to primarily detect substrate vibration via connections between the lower jaw and the inner ear. We used the western rat snake (Pantherophis obsoletus) to determine how vibration is processed in the brain. We measured vibration-evoked potential recordings to reveal sensitivity to low-frequency vibrations. We then used tract tracing combined with immunohistochemistry and Nissl staining to describe the central projections of the papillar branch of the VIIIth nerve. Applications of biotinylated dextran amine to the basilar papilla (homologous to the organ of Corti of mammals) labeled bouton-like terminals in two first-order cochlear nuclei, a rostrolateral nucleus angularis (NA) and a caudomedial nucleus magnocellularis (NM). NA formed a distinct dorsal eminence, consisted of heterogenous cell types, and was parvalbumin positive. NM was smaller and poorly separated from the surrounding vestibular nuclei. NM was distinguished by positive calbindin label and included fusiform and round cells. Thus, the atympanate western rat snake shares similar first-order projections to tympanate reptiles. Auditory pathways may be used for detecting vibration, not only in snakes but also potentially in atympanate early tetrapods.

Age-related changes in basal forebrain afferent activation in response to food paired stimuli.

The basal forebrain contains a phenotypically-diverse assembly of neurons, including those using acetylcholine as their neurotransmitter. This basal forebrain cholinergic system projects to the entire neocortical mantle as well as subcortical limbic structures that include the hippocampus and amygdala. Basal forebrain pathology, including cholinergic dysfunction, is thought to underlie the cognitive impairments associated with several age-related neurodegenerative conditions, including Alzheimer's disease. Basal forebrain dysfunction may stem, in part, from a failure of normal afferent regulation of cholinergic and other neurons in this area. However, little is understood regarding how aging, alone, affects the functional regulation of basal forebrain afferents in the context of motivated behavior. Here, we used neuronal tract-tracing combined with motivationally salient stimuli in an aged rodent model to examine how aging alters activity in basal forebrain inputs arising from several cortical, limbic and brainstem structures. Young rats showed greater stimulus-associated activation of basal forebrain inputs arising from prelimbic cortex, nucleus accumbens and the ventral tegmental area compared with aged rats. Aged rats also showed increased latency to respond to palatable food presentation compared to young animals. Changes in activation of intrinsic basal forebrain cell populations or afferents were also observed as a function of age or experimental condition. These data further demonstrate that age-related changes in basal forebrain activation and related behavioral and cognitive functions reflect a failure of afferent regulation of this important brain region.

The Cerebellar Cortex Receives Orofacial Proprioceptive Signals from the Supratrigeminal Nucleus via the Mossy Fiber Pathway in Rats.

Proprioceptive sensory information from muscle spindles is essential for the regulation of motor functions. However, little is known about the motor control regions in the cerebellar cortex that receive proprioceptive signals from muscle spindles distributed throughout the body, including the orofacial muscles. Therefore, in this study, we investigated the pattern of projections in the rat cerebellar cortex derived from the supratrigeminal nucleus (Su5), which conveys orofacial proprioceptive information from jaw-closing muscle spindles (JCMSs). Injections of an anterograde tracer into the Su5 revealed that many bilateral axon terminals (rosettes) were distributed in the granular layer of the cerebellar cortex (including the simple lobule B, crus II and flocculus) in a various sized, multiple patchy pattern. We could also detect JCMS proprioceptive signals in these cerebellar cortical regions, revealing for the first time that they receive muscle proprioceptive inputs in rats. Retrograde tracer injections confirmed that the Su5 directly sends outputs to the cerebellar cortical areas. Furthermore, we injected an anterograde tracer into the external cuneate nucleus (ECu), which receives proprioceptive signals from the forelimb and neck muscle spindles, to distinguish between the Su5- and ECu-derived projections in the cerebellar cortex. The labeled terminals from the ECu were distributed predominantly in the vermis of the cerebellar cortex. Almost no overlap was seen in the terminal distributions of the Su5 and ECu projections. Our findings demonstrate that the rat cerebellar cortex receives orofacial proprioceptive input that is processed differently from the proprioceptive signals from the other regions of the body.

Leveling up: a long-range olivary projection to the medial geniculate without collaterals to the central nucleus of the inferior colliculus in rats.

The medial nucleus of the trapezoid body (MNTB) is one of the monaural cell groups situated within the superior olivary complex (SOC), a constellation of brainstem nuclei with numerous roles in hearing. Principal MNTB neurons are glycinergic and express the calcium-binding protein, calbindin (CB). The MNTB receives its main glutamatergic, excitatory input from the contralateral cochlear nucleus via the calyx of Held and converts this into glycinergic inhibition directed toward nuclei in the SOC and the ventral and intermediate nuclei of the lateral lemniscus (VNLL and INLL). Through this inhibition, the MNTB plays essential roles in localization of sound sources and encoding spectral and temporal features of sound. In rats, very few MNTB neurons project to the inferior colliculus. However, our recent study of SOC projections to the auditory thalamus revealed a substantial number of retrogradely labeled MNTB neurons. This observation led us to examine whether the rat MNTB provides a long-range projection to the medial geniculate body (MGB). We examined this possible projection using retrograde and anterograde tract tracing and immunohistochemistry for CB and the glycine receptor. Our results demonstrate a significant projection to the MGB from the ipsilateral MNTB that does not involve a collateral projection to the inferior colliculus.

Phosphodiesterase 10A deactivation induces long-term neurological recovery, Peri-infarct remodeling and pyramidal tract plasticity after transient focal cerebral ischemia in mice.

The phosphodiesterase (PDE) superfamily comprises enzymes responsible for the cAMP and cGMP degradation to AMP and GMP. PDEs are abundant in the brain, where they are involved in several neuronal functions. High PDE10A abundance was previously observed in the striatum; however its consequences for stroke recovery were unknown. Herein, we evaluated the effects of PDE10A deactivation by TAK-063 (0.3 or 3 mg/kg, initiated 72 h post-stroke) in mice exposed to intraluminal middle cerebral artery occlusion. We found that PDE10A deactivation over up to eight weeks dose-dependently increased long-term neuronal survival, angiogenesis, and neurogenesis in the peri-infarct striatum, which represents the core of the middle cerebral artery territory, and reduced astroglial scar formation, whole brain atrophy and, more specifically, striatal atrophy. Functional motor-coordination recovery and the long-distance plasticity of pyramidal tract axons, which originate from the contralesional motor cortex and descend through the contralesional striatum to innervate the ipsilesional facial nucleus, were enhanced by PDE10A deactivation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed a set of dopamine receptor-related and neuronal plasticity-related PDE10A targets, which were elevated (e.g., protein phosphatase-1 regulatory subunit 1B) or reduced (e.g., serine/threonine protein phosphatase 1α, ß-synuclein, proteasome subunit α2) by PDE10A deactivation. Our results identify PDE10A as a therapeutic target that critically controls post-ischemic brain tissue remodeling and plasticity.

Prenatal androgen treatment impairs the suprachiasmatic nucleus arginine-vasopressin to kisspeptin neuron circuit in female mice.

Polycystic ovary syndrome (PCOS) is associated with elevated androgen and luteinizing hormone (LH) secretion and with oligo/anovulation. Evidence indicates that elevated androgens impair sex steroid hormone feedback regulation of pulsatile LH secretion. Hyperandrogenemia in PCOS may also disrupt the preovulatory LH surge. The mechanisms through which this might occur, however, are not fully understood. Kisspeptin (KISS1) neurons of the rostral periventricular area of the third ventricle (RP3V) convey hormonal cues to gonadotropin-releasing hormone (GnRH) neurons. In rodents, the preovulatory surge is triggered by these hormonal cues and coincident timing signals from the central circadian clock in the suprachiasmatic nucleus (SCN). Timing signals are relayed to GnRH neurons, in part, via projections from SCN arginine-vasopressin (AVP) neurons to RP3VKISS1 neurons. Because rodent SCN cells express androgen receptors (AR), we hypothesized that these circuits are impaired by elevated androgens in a mouse model of PCOS. In prenatally androgen-treated (PNA) female mice, SCN Ar expression was significantly increased compared to that found in prenatally vehicle-treated mice. A similar trend was seen in the number of Avp-positive SCN cells expressing Ar. In the RP3V, the number of kisspeptin neurons was preserved. Anterograde tract-tracing, however, revealed reduced SCNAVP neuron projections to the RP3V and a significantly lower proportion of RP3VKISS1 neurons with close appositions from SCNAVP fibers. Functional assessments showed, on the other hand, that RP3VKISS1 neuron responses to AVP were maintained in PNA mice. These findings indicate that PNA changes some of the neural circuits that regulate the preovulatory surge. These impairments might contribute to ovulatory dysfunction in PNA mice modeling PCOS.

Sex differences in the amygdaloid projections to the ventrolateral periaqueductal gray and their activation during inflammatory pain in the rat.

Preclinical and clinical studies have reported sex differences in pain and analgesia. These differences may be linked to anatomical structures of the central nervous system pain modulatory circuitry, and/or hormonal milieu. The midbrain periaqueductal gray (PAG) is a critical brain region for descending inhibition of pain. The PAG projects to the rostral ventromedial medulla (RVM), which projects bilaterally to the spinal cord to inhibit pain. In addition to pain, this descending circuit (or pathway) can be engaged by endogenous opioids (i.e., endorphins) or exogenous opioids (i.e., morphine), and we have previously reported sex differences in the activation of this circuit during pain and analgesia. Forebrain structures, including the amygdala, project to and engage the PAG-RVM circuit during persistent inflammatory pain. However, there are limited studies in females detailing this amygdalar-PAG pathway and its involvement during persistent inflammatory pain. The objective of the present study was to delineate the neural projections from the amygdala to the PAG in male and female rats to determine if they are sexually distinct in their anatomical organization. We also examined the activation of this pathway by inflammatory pain and the co-localization of receptors for estrogen. Injection of the retrograde tracer fluorogold (FG) into the ventrolateral PAG (vlPAG) resulted in dense retrograde labeling in both the central amygdala (CeA) and medial amygdala (MeA). While the number of CeA-vlPAG neurons were comparable between the sexes, there were more MeA-vlPAG neurons in females. Inflammatory pain resulted in greater activation of the amygdala in males; however, females displayed higher Fos expression within CeA-vlPAG projection neurons. Females expressed higher ERα in the MeA and CeA and the same was true of the projection neurons. Together, these data indicate that although the MeA-vlPAG projections are denser in females, inflammatory pain does not significantly activate these projections. In contrast, inflammatory pain resulted in a greater activation of the CeA-vlPAG pathway in females. As females experience a greater number of chronic pain syndromes, the CeA-vlPAG pathway may play a facilitatory (and not inhibitory) role in pain modulation.