Biology subjects

Wesson, D. W.

Publications and source records attributed to Wesson, D. W..

13 recordsLinked to original sources

bioRxiv2026

Disruption of opioid and mesolimbic dopamine dynamics and behavior upon intranasal delivery of opioids in mice

The endogenous opioid system, consisting of mu, delta, and kappa opioid receptors, along with naturally occurring peptides, is central for regulating reward processing, mood, motivation, and social attachment. Endogenous opioids, as well as opioid drugs that are administered clinically or are misused/abused, are potent modulators of several neurotransmitter systems in the brain, including dopamine (DA). Since the opioid system is dysregulated in neuropsychiatric conditions, and opioids are prevalently misused/abused to achieve altered affective and cognitive states, the understanding of the mechanisms of action of opioids is highly significant. Unfortunately, there is no pre-clinical approach for understanding the actions of intranasally (IN) administered opioids, a common route of administration by both individuals with opioid use disorder and a route used clinically to achieve reversal of opioid overdose. Here we combined reliable and precise delivery of opioids into the nasal cavity of mice together with measures of opioid and DA dynamics in the nucleus accumbens (NAc) with fiber photometry, or, with measures of behaviors known impacted by opioids following other routes of administration, including respiration, to demonstrate the outcomes of IN opioids in mice. We uncovered a prompt and prolonged increase in mesolimbic DA by both IN morphine and fentanyl and the restoration of DA to baseline levels by subsequent IN opioid receptor antagonism with naloxone. Simultaneously, IN morphine and fentanyl each resulted in a short-lasting increase in NAc opioid dynamics. Next, in separate mice, we found that IN opioids elicit rapid canonical opioid-induced behaviors, including respiratory depression, which were rapidly reversed by IN naloxone. Overall, this work establishes a sensitive approach for evaluating the neural circuitry underlying opioid use disorder in a manner which recapitulates IN opioid use with ecological validity. Moreover, our findings point towards a likely important role for mesolimbic DA in mediating opioid overdose reversal.

neuroscience↗

bioRxiv2025

In-dwelling microfluidic device for precise and reliable intranasal drug delivery during freely-moving behavior

Many substances/drugs are administered intranasally (IN). These include opioid overdose reversal drugs, anti-epileptic medications, migraine medications, hormone treatments, and medicines to treat/prevent allergies, colds, and flues including nasally-administered vaccines, corticosteroids, antihistamines, and decongestants. Additionally, IN administration is the preferred route of entry by users of illicit drugs. Despite the widespread use of the IN route of administration, there is no established paradigm to access this route of administration preclinically to yield precise and reliable control over delivery. This poses major gaps in therapeutic discovery/testing, establishing pharmacokinetic/pharmacodynamic relationships of therapeutics, and understanding the mechanisms of actions of therapeutics. We developed an in-dwelling microfluidic device, that, when implanted upon the nasal bone, accesses the nasal cavity to allow reliable and precise IN fluid delivery during freely-moving behavior. We validated this device, called the Nasal Access Port (NAP), to confirm it allows rapid and precise control of fluids. We further exemplified the application of the NAP for studying outcomes of IN cocaine in mice, including its pharmacokinetic profile, and both the rapid release of dopamine (DA) and behavioral effects upon IN cocaine. By achieving precise and reliable access to the IN route of administration, the NAP represents a significant methodological advance with broad applicability in the biomedical and life sciences, especially in the neuroscience, pharmacology, medicinal chemistry, and physiology domains.

pharmacology and toxicology↗

bioRxiv2024

Brain-body circuit by which midbrain dopamine neuronal activity modulates splenic immunity

Midbrain dopamine neurons are well-known to shape central nervous system function, yet there is growing evidence for their influence on the peripheral immune system. Here we demonstrate that midbrain dopamine neurons form a circuit to the spleen via a multi-synaptic pathway from the dorsal vagal complex (DVC) through the celiac ganglion. Midbrain dopamine neurons modulate the activity of D1- and D2-like dopamine receptor-expressing DVC neurons. In vivo activation of midbrain dopamine neurons induced dopamine release in the DVC and increased immediate early gene expression in both the DVC and celiac ganglion. Activation of this midbrain-to-spleen circuit reduced spleen weight and decreased naive CD4+ T-cell populations without affecting total T-cell numbers. These findings unveil a functional midbrain- DVC-celiac ganglion-spleen pathway, through which midbrain dopamine neurons modulate splenic immunity. These novel insights into the neural regulation of the immune system have important implications for diseases involving altered dopamine neurotransmission and highlight potential targets for immunotherapeutic interventions.

neuroscience↗

bioRxiv2024

Sniffing is initiated by the actions of dopamine on ventral striatum neurons

Sniffing is a motivated behavior displayed by nearly all terrestrial vertebrates. While sniffing is associated with acquiring and processing odors, sniffing is also intertwined with affective and motivated states. The neuromodulatory systems which influence the display of sniffing are unclear. Here, we report that dopamine release into the ventral striatum is coupled with bouts of sniffing and that stimulation of dopaminergic terminals in these regions drives increases in respiratory rate to initiate sniffing whereas inhibition of these terminals reduces respiratory rate. Both the firing of individual neurons and the activity of post-synaptic D1 and D2 receptor-expressing neurons in the ventral striatum are also coupled with sniffing and local antagonism of D1 and D2 receptors squelches sniffing. Together, these results support a model whereby sniffing can be initiated by dopamines actions upon ventral striatum neurons. The nature of sniffing being integral to both olfaction and motivated behaviors implicates this circuit in a wide array of functions.

neuroscience↗

bioRxiv2022

Glucagon-like peptide-1 receptors in the gustatory cortex influence food intake

The gustatory region of the insular cortex (GC) processes taste information in manners important for taste-guided behaviors, including food intake itself. In addition to oral gustatory stimuli, GC activity is also influenced by physiological states including hunger. The specific cell-types and molecular mechanisms that afford with GC with such influences on food intake are unclear. Glucagon-like peptide 1 (GLP-1) is produced by neurons in the brain whereafter it can act upon GLP-1 receptor-expressing (GLP-1R+) neurons found in several brain regions. In these brain regions, GLP-1R agonism suppresses homeostatic food intake and dampens the hedonic value of food. Here, we report in mice of both sexes that cells within the GC express GLP-1R mRNA and further, by ex vivo brain slice recordings, that GC GLP-1R+ neurons are depolarized by the selective GLP-1R agonist, exendin-4 (Ex-4). Next we found that chemogenetic stimulation of GLP-1R+ neurons, and also pharmacological stimulation of GC-GLP-1Rs themselves, both reduced homeostatic food intake. When maintained on a high-fat diet, obese mice exhibited impaired food intake responses when Ex-4 was administered into the GC. Yet, when obese mice were switched to a low-fat diet, the effect of GC Ex-4 was restored - indicating that GC GLP-1R influences may depend upon palatability of the food. Together, these results provide evidence for a specific cell population in the GC which may hold roles in both homeostatic and hedonic food intake.

neuroscience↗

bioRxiv2021

Self-grooming promotes social interaction in mice via chemosensory communication

Self-grooming is a stereotyped behavior displayed by nearly all animals. Among other established functions, self-grooming is implicated in social communication in some animals. However, whether self-grooming specifically influences behaviors of nearby individuals has not been directly tested, partly due to the technical challenge of inducing self-grooming in a reliable and temporally controllable manner. We recently found that optogenetic activation of dopamine D3 receptor expressing neurons in the ventral striatal islands of Calleja robustly induces orofacial grooming in mice. Using this optogenetic manipulation, here we demonstrate that observer mice exhibit social preference for mice that groom more regardless of biological sex. Moreover, grooming-induced social attraction depends on volatile chemosensory cues broadcasted from grooming mice. Collectively, our study establishes self-grooming as a means of promoting social attraction among mice via volatile cues, suggesting an additional benefit for animals to allocate a significant amount of time to this behavior.

neuroscience↗

bioRxiv2021

Organization and engagement of a prefrontal-olfactory network during olfactory selective attention

Sensory perception is profoundly shaped by attention. Attending to an odor strongly regulates if and how a smell is perceived - yet the brain systems involved in this process are unknown. Here we report integration of the medial prefrontal cortex (mPFC), a collection of brain regions integral to attention, with the olfactory system in the context of selective attention to odors. First, we used tracing methods to establish the tubular striatum (TuS, also known as the olfactory tubercle) as the primary olfactory region to receive direct mPFC input in rats. Next, we recorded local field potentials from the olfactory bulb (OB), mPFC, and TuS while rats completed an olfactory selective attention task. Gamma power and coupling of gamma oscillations with theta phase were consistently high as rats flexibly switched their attention to odors. Beta and theta synchrony between mPFC and olfactory regions were elevated as rats switched their attention to odors. Finally, we found that sniffing was consistent despite shifting attentional demands, suggesting that the mPFC-OB theta coherence is independent of changes in active sampling. Together, these findings begin to define an olfactory attention network wherein mPFC activity, as well as that within olfactory regions, are coordinated in manners based upon attentional states.

neuroscience↗

bioRxiv2020

Alterations in odor hedonics in the Tg6799 Alzheimer's disease mouse model and the influence of sex

Olfactory impairments, including deficits in odor detection, discrimination, recognition, and changes in odor hedonics are reported in the early stages of Alzheimers disease (AD). Rodent models of AD display deficits in odor learning, detection, and discrimination - recapitulating the clinical condition. However, the impact of familial AD genetic mutations on odor hedonics is unknown. We tested 2-, 4-, and 6-months old 5XFAD (Tg6799) mice in the five-port odor multiple-choice task designed to assay a variety of odor-guided behaviors, including odor preferences/hedonics. We found that 5XFAD mice investigated odors longer than controls, an effect that was driven by 6-months old mice. Interestingly, this effect was carried by females in the 5XFAD group, who investigated odors longer than age-matched males. Upon examining behavior directed towards individual odors to test for aberrant odor preferences, we uncovered that 5XFAD females at several ages displayed heightened preferences towards some of the odors, indicating aberrant hedonics. We observed no impairments in the ability to engage in the task in 5XFAD mice. Taken together, 5XFAD mice, particularly 5XFAD females, displayed prolonged odor investigation behavior and enhanced preferences to certain odors. The data provide insight into hedonic alterations which may occur in AD mouse models, and how these are influenced by biological sex.

neuroscience↗

bioRxiv2020

α-Synuclein perturbs in vivo neural activity following seeding in the olfactory bulb

BACKGROUNDParkinsons disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded -Synuclein (-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of -Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. -Syn fibrils injected into the OB of mice cause progressive propagation of -Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits. OBJECTIVEWe hypothesized that accumulation of pathogenic -Syn in the OB impairs neural activity in the olfactory system. METHODSTo address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed -Syn fibrils in the OB. RESULTSWe detected -Syn pathology in both the OB and PCX. We also observed that -Syn fibril injections influenced odor-evoked activity in the OB. In particular, -Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of -Syn pathology. CONCLUSIONSTogether, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.

neuroscience↗

bioRxiv2020

Deficits in olfactory sensitivity in a mouse model of Parkinson's disease revealed by plethysmography of odor-evoked sniffing

Hyposmia is evident in over 90% of Parkinsons disease (PD) patients. A characteristic of PD is intraneuronal deposits composed in part of -synuclein fibrils. Based on the analysis of post-mortem PD patients, Braak and colleagues suggested that early in the disease -synuclein pathology is present in the dorsal motor nucleus of the vagus, as well as the olfactory bulb and the anterior olfactory nucleus, and then later affects other interconnected brain regions. Here, we bilaterally injected -synuclein preformed fibrils into the olfactory bulb of wild type male and female mice. Six-months after injection, the anterior olfactory nucleus and the piriform cortex displayed a high -synuclein pathology load. We evaluated olfactory perceptual function by monitoring odor-evoked sniffing behavior in a plethysmograph at one-, three- and six-months after injection of -synuclein fibrils. At all-time points, females injected with fibrils exhibited reduced odor detection sensitivity, which was detectable with the semi-automated plethysmography apparatus, but not a buried pellet test. In future studies, this sensitive methodology we used to assess olfactory detection deficits could be used to define how -synuclein pathology affects other aspects of olfactory perception in PD models and to clarify the neuropathological underpinnings of these deficits. Highlights- -synuclein pathology spreads through neuronally-connected areas after bilateral injection of preformed fibrils into the olfactory bulb. - A plethysmograph and an olfactometer were used for a semi-automated screen of odor-evoked sniffing as an assay for odor detection sensitivity. - Bilateral olfactory bulb injections of -synuclein preformed fibrils in female mice led to reduced sensitivity for detecting odors. - The semi-automated plethysmography apparatus was more sensitive at detecting odor detection deficits than the buried pellet test.

neuroscience↗

bioRxiv2019

A neural system for encoding odor-reward associations which influences approach behaviors

Learning strengthens the strong emotional and behavioral responses odors are well known for eliciting. Presumably subserving this, several brain regions display experience-dependent plasticity during odor learning, yet the specific cellular systems involved and the actual influence of these systems on odor-directed behavior are less understood. Here we investigated the transformation of odor information throughout the association of odors with rewards and also sought to link those neural systems with displays of reinforcement-based task engagement. First, we investigated the representation of odor-reward associations within two areas recipient of dense olfactory bulb input, the posterior piriform cortex (pPCX) and olfactory tubercle (OT), using simultaneous multi-site electrophysiological recordings from mice engaged in a reward-based olfactory learning task. As expected, neurons in both regions represented conditioned odors and did so with similar information content, yet both the proportion of neurons recruited by conditioned rewarded odors and the magnitudes and durations of their responses were greater in the OT. Using fiber photometry, we found that OT D1-type dopamine receptor expressing neurons flexibly represent odors based upon reward associations. In both the recordings and imaging, statistically meaningful changes in activity occurred soon after odor onset. Finally, using optogenetics we show that OT D1-receptor expressing neurons strongly influence behavior to promote task engagement. Together our results contribute to a model whereby OT D1 neurons support odor-guided motivated behaviors.

neuroscience↗

bioRxiv2017

Selective attention controls olfaction in rodents

Critical animal behaviors, especially among rodents, are guided by odors in remarkably well-coordinated manners. While many extramodal sensory cues compete for cognitive resources in these ecological contexts, that rodents can engage in such odor-guided behaviors suggests that they selectively attend to odors. We developed a behavioral paradigm to reveal that rats are indeed capable of selectively attending to odors in the presence of competing extramodal stimuli and found that this selective attention facilitates accurate odor-guided decisions. Further, we uncovered that attention to odors adaptively sharpens their representation among neurons in a brain region considered integral for odor-driven behaviors. Thus, selective attention contributes to olfaction by enhancing the coding of odors in a manner analogous to that observed among other sensory systems.

neuroscience↗

bioRxiv2017

A cortical pathway modulates sensory input into the olfactory striatum

Sensory cortices process stimuli in manners essential for perception. The piriform primary olfactory cortex (PCX) extends dense association fibers into the ventral striatums olfactory tubercle (OT), yet the function of this cortico-striatal pathway is unknown. We optically stimulated channelrhodopsin-transduced PCX glutamatergic neurons or their association fibers while recording OT neural activity in mice performing an olfactory task. Activation of PCX neurons or their association fibers within the OT controlled the firing of some OT neurons and bidirectionally modulated odor coding dependent upon the neurons intrinsic odor responsivity. Further, patch clamp recordings and retroviral tracing from D1 and D2 dopamine receptor-expressing OT medium spiny neurons revealed this input can be monosynaptic and that both cell types receive most of their input from a specific spatial zone localized within the ventro-caudal PCX. These results demonstrate that the PCX functionally accesses the direct and indirect pathways of the basal ganglia within the OT.

neuroscience↗