The research featured on this page has been funded in part by the Chernowitz Medical Research Foundation.

Frontiers in Behavioral Neuroscience | 27 January 2023 | https://doi.org/10.3389/fnbeh.2022.1092420

Dopaminergic regulation of hippocampal plasticity, learning, and memory

Theodoros Tsetsenis | John I. Broussard | John A. Dani

Abstract:

The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.

Frontiers in Cellular Neuroscience | 15 April 2022 | https://doi.org/10.3389/fncel.2022.887679

Activation of a Locus Coeruleus to Dorsal Hippocampus Noradrenergic Circuit Facilitates Associative Learning

Theodoros Tsetsenis | Julia K. Badyna | Rebecca Li | John A. Dani

Abstract:

Processing of contextual information during a new episodic event is crucial for learning and memory. Neuromodulation in the hippocampus and prefrontal cortex plays an important role in the formation of associations between environmental cues and an aversive experience. Noradrenergic neurons in the locus coeruleus send dense projections to both regions, but their contribution to contextual associative learning has not been established. Here, we utilize selective optogenetic and pharmacological manipulations to control noradrenergic transmission in the hippocampus during the encoding of a contextual fear memory. We find that boosting noradrenergic terminal release in the dorsal CA1 enhances the acquisition of contextual associative learning and that this effect requires local activation of β-adrenenergic receptors. Moreover, we show that increasing norepinephrine release can ameliorate contextual fear learning impairments caused by dopaminergic dysregulation in the hippocampus. Our data suggest that increasing of hippocampal noradrenergic activity can have important implications in the treatment of cognitive disorders that involve problems in contextual processing.

Addiction Biology | 10 February 2022 | https://doi.org/10.1111/adb.13147

The serotonin 2A receptor agonist TCB-2 attenuates heavy alcohol drinking and alcohol-induced midbrain inhibitory plasticity

Blake A. Kimmey | Ruthie E. Wittenberg | Alexandra Croicu | Nikita Shadani | Alexey Ostroumov | John A. Dani

Abstract:

Disruption of neuronal chloride ion (Cl) homeostasis has been linked to several pathological conditions, including substance use disorder, yet targeted pharmacotherapies are lacking. In this study, we explored the potential of serotonin 2A receptor (5-HT2AR) agonism to reduce alcohol consumption in male wild-type C57Bl/6J mice and to ameliorate alcohol-induced inhibitory plasticity in the midbrain. We found that administration of the putative 5-HT2AR agonist TCB-2 attenuated alcohol consumption and preference but did not alter water or saccharin consumption. We hypothesized that the selective behavioural effects of TCB-2 on alcohol drinking were due, at least in part, to effects of the agonist on ventral tegmental area (VTA) neurocircuitry. Alcohol consumption impairs Cl transport in VTA GABA neurons, which acts as a molecular adaptation leading to increased alcohol self-administration. Using ex vivo electrophysiological recordings, we found that exposure to either intermittent volitional alcohol drinking or an acute alcohol injection diminished homeostatic Cl transport in VTA GABA neurons. Critically, in vivo TCB-2 administration normalized Cl transport in the VTA after alcohol exposure. Thus, we show a potent effect of alcohol consumption on VTA inhibitory circuitry, in the form of dysregulated Cl homeostasis that is reversible with agonism of 5-HT2ARs. Our results provide insight into the potential therapeutic action of 5-HT2AR agonists for alcohol abuse.

PNAS | 27 September 2021 | https://doi.org/10.1073/pnas.2111069118

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

Theodoros Tsetsenis | Julia K. Badyna | Julianne A. Wilson | Xiaowen Zhang | Elizabeth N. Krizman | Manivannan Subramaniyan | Kechun Yang | Steven A. Thomas | John A. Dani

Abstract:

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

Addiction Biology | 7 April 2020 | https://doi.org/10.1111/adb.12899

Ethanol produces multiple electrophysiological effects on ventral tegmental area neurons in freely moving rats

William M. Doyon | Alexey Ostroumov | Tiahna Ontiveros | Rueben A. Gonzales | John A. Dani

Abstract:

Although alcohol (i.e., ethanol) is a major drug of abuse, the acute functional effects of ethanol on the reward circuitry are not well defined in vivo. In freely moving rats, we examined the effect of intravenous ethanol administration on neuronal unit activity in the posterior ventral tegmental area (VTA), a central component of the mesolimbic reward system. VTA units were classified as putative dopamine (DA) neurons, fast-firing GABA neurons, and unidentified neurons based on a combination of electrophysiological properties and DA D2 receptor pharmacological responses. A gradual infusion of ethanol significantly altered the firing rate of DA neurons in a concentration-dependent manner. The majority of DA neurons were stimulated by ethanol and showed enhanced burst firing activity, but a minority was inhibited. Ethanol also increased the proportion of DA neurons that exhibited pacemaker-like firing patterns. In contrast, ethanol mediated a variety of effects in GABA and other unidentified neurons that were distinct from DA neurons, including a nonlinear increase in firing rate, delayed inhibition, and more biphasic activity. These results provide evidence of discrete electrophysiological effects of ethanol on DA neurons compared with other VTA cell types, suggesting a complex role of the VTA in alcohol-induced responses in freely moving animals.

eNeuro | 26 February 2020 | https://doi.org/10.1523/ENEURO.0348-19.2020

Acute Nicotine Exposure Alters Ventral Tegmental Area Inhibitory Transmission and Promotes Diazepam Consumption

Alexey Ostroumov | Ruthie E. Wittenberg | Blake A. Kimmey | Madison B. Taormina | William M. Holden | Albert T. McHugh | John A. Dani

Abstract:

Nicotine use increases the risk for subsequent abuse of other addictive drugs, but the biological basis underlying this risk remains largely unknown. Interactions between nicotine and other drugs of abuse may arise from nicotine-induced neural adaptations in the mesolimbic dopamine (DA) system, a common pathway for the reinforcing effects of many addictive substances. Previous work identified nicotine-induced neuroadaptations that alter inhibitory transmission in the ventral tegmental area (VTA). Here, we test whether nicotine-induced dysregulation of GABAergic signaling within the VTA increases the vulnerability for benzodiazepine abuse that has been reported in smokers. We demonstrate in rats that nicotine exposure dysregulates diazepam-induced inhibition of VTA GABA neurons and increases diazepam consumption. In VTA GABA neurons, nicotine impaired KCC2-mediated chloride extrusion, depolarized the GABAA reversal potential, and shifted the pharmacological effect of diazepam on GABA neurons from inhibition toward excitation. In parallel, nicotine-related alterations in GABA signaling observed ex vivo were associated with enhanced diazepam-induced inhibition of lateral VTA DA neurons in vivo. Targeting KCC2 with the agonist CLP290 normalized diazepam-induced effects on VTA GABA transmission and reduced diazepam consumption following nicotine administration to the control level. Together, our results provide insights into midbrain circuit alterations resulting from nicotine exposure that contribute to the abuse of other drugs, such as benzodiazepines.

Frontiers in Immunology | 26 July 2023 | https://doi.org/10.3389/fimmu.2023.1201619

The podocyte: glomerular sentinel at the crossroads of innate and adaptive immunity

George W. Burke III | Alla Mitrofanova | Antonio Fontanella | Gaetano Ciancio | David Roth | Phil Ruiz | Caroline Abitbol | Jayanthi Chandar | Sandra Merscher | Alessia Fornoni

Abstract:

Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with the nephrotic syndrome and has a propensity to recur following kidney transplantation. The pathophysiology and therapies available to treat FSGS currently remain elusive. Since the podocyte appears to be the target of apparent circulating factor(s) that lead to recurrence of proteinuria following kidney transplantation, this article is focused on the podocyte. In the context of kidney transplantation, the performance of pre- and post-reperfusion biopsies, and the establishment of in vitro podocyte liquid biopsies/assays allow for the development of clinically relevant studies of podocyte biology. This has given insight into new pathways, involving novel targets in innate and adaptive immunity, such as SMPDL3b, cGAS-STING, and B7-1. Elegant experimental studies suggest that the successful clinical use of rituximab and abatacept, two immunomodulating agents, in our case series, may be due to direct effects on the podocyte, in addition to, or perhaps distinct from their immunosuppressive functions. Thus, tissue biomarker-directed therapy may provide a rational approach to validate the mechanism of disease and allow for the development of new therapeutics for FSGS. This report highlights recent progress in the field and emphasizes the importance of kidney transplantation and recurrent FSGS (rFSGS) as a platform for the study of primary FSGS.

Cells | 16 November 2022 | https://doi.org/10.3390/cells11223635

Mitochondrial Contribution to Inflammation in Diabetic Kidney Disease

Alla Mitrofanova | Antonio M. Fontanella | George W. Burke | Sandra Merscher | Alessia Fornoni

Abstract:

Diabetes is the leading cause of chronic kidney disease worldwide. Despite the burden, the factors contributing to the development and progression of diabetic kidney disease (DKD) remain to be fully elucidated. In recent years, increasing evidence suggests that mitochondrial dysfunction is a pathological mediator in DKD as the kidney is a highly metabolic organ rich in mitochondria. Furthermore, low grade chronic inflammation also contributes to the progression of DKD, and several inflammatory biomarkers have been reported as prognostic markers to risk-stratify patients for disease progression and all-cause mortality. Interestingly, the term “sterile inflammation” appears to be used in the context of DKD describing the development of intracellular inflammation in the absence of bacterial or viral pathogens. Therefore, a link between mitochondrial dysfunction and inflammation in DKD exists and is a hot topic in both basic research and clinical investigations. This review summarizes how mitochondria contribute to sterile inflammation in renal cells in DKD.

Journal of the American Society of Nephrology | 5 October 2022 | https://doi.org/10.1681/asn.2021101286 

Activation of Stimulator of IFN Genes (STING) Causes Proteinuria and Contributes to Glomerular Diseases.

Alla Mitrofanova | Antonio Fontanella | Matthew Tolerico | Shamroop Mallela | Judith Molina David | Yiqin Zuo | Marcia Boulina | Jin-Ju Kim | Javier Santos | Mengyuan Ge | Alexis Sloan | Wadih Issa | Margaret Gurumani | Jeffrey Pressly | Marie Ito | Matthias Kretzler | Sean Eddy | Robert Nelson | Sandra Merscher | George Burke | Alessia Fornoni

Abstract:

Background

The signaling molecule stimulator of IFN genes (STING) was identified as a crucial regulator of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-STING pathway, and this signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI. However, the role of STING in causing CKD, including diabetic kidney disease (DKD) and Alport syndrome, is unknown.

Methods

To investigate whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome, immortalized human and murine podocytes were differentiated for 14 days and treated with a STING-specific agonist. We used diabetic db/db mice, mice with experimental Alport syndrome, C57BL/6 mice, and STING knockout mice to assess the role of the STING signaling pathway in kidney failure.

Results

In vitro, murine and human podocytes express all of the components of the cGAS-STING pathway. In vivo, activation of STING renders C57BL/6 mice susceptible to albuminuria and podocyte loss. STING is activated at baseline in mice with experimental DKD and Alport syndrome. STING activation occurs in the glomerular but not the tubulointerstitial compartment in association with autophagic podocyte death in Alport syndrome mice and with apoptotic podocyte death in DKD mouse models. Genetic or pharmacologic inhibition of STING protects from progression of kidney disease in mice with DKD and Alport syndrome and increases lifespan in Alport syndrome mice.

Conclusion

The activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Targeting STING may offer a therapeutic option to treat glomerular diseases of metabolic and nonmetabolic origin or prevent their development, progression, or both.