Florey Department of Neuroscience and Mental Health - Theses
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ItemThe utility of genetic animal models to investigate early disease states in Parkinson’s disease using translatable biomarkers( 2023-09)Parkinson’s disease (PD) is the fastest growing form of dementia, with over 9.4 million people living with the condition in 2020. PD is characterised by the motor impairments, bradykinesia, rigidity and tremors, and results in life-long disability. Despite the first report of PD being 200 years ago, there is still no disease modifying treatments. Current hypotheses point to diagnosis occurring too late, as 50-90% of dopaminergic neurons that cause the hallmark motor symptoms, have been lost by the time of diagnosis. Prodromal PD encapsulates an extended period of time up to 20 years prior to the onset of overt motor impairment where many non-motor symptoms and non-dopaminergic pathologies occur. These include accumulation of iron or white matter microstructural changes. Identifying these changes in the prodromal phase using biomarkers may represent an opportunity to target earlier in the disease course. Animal models of PD have been pivotal in understanding disease mechanisms and are necessary to validate potential biomarkers with underlying pathomechanisms. This thesis investigated the utility of genetic animal models of PD to investigate several translatable biomarkers in early disease states. The first study systematically reviewed the preclinical literature that examined non-motor phenotypes aligning with the MDS criteria for prodromal PD in all genetic rodent models of PD. The results demonstrated a significant literature gap as the presence of most phenotypes across many models were inconclusive due to assessments at different ages, variability in experimental or environmental factors and inadequate studies. The A53T mouse model and wild-type human alpha-synuclein overexpression model were highlighted as the models that recapitulated the most non-motor phenotypes. From the results of the systematic review, the A53T mouse model was chosen to further investigate neuroimaging biomarkers in the second and third study. The second study investigated if the MRI technique, quantitative iii susceptibility mapping (QSM), could be used to determine iron content in the A53T mouse brain as iron deposition has shown to be implicated in PD neuropathology. The perfused brains of A53T and wildtype mice were scanned at 5, 7 and 9 months to evaluate longitudinal changes in four PD-associated brain regions. Susceptibility output was used as an estimated measure of iron and was validated with a quantified iron measure by mass spectrometry in four PD-associated brain regions. These were the substantia nigra (SN), caudate putamen, hippocampus and cortex. The findings of this study revealed A53T mice did not have increased iron compared to wildtypes at any age. QSM was confirmed as a valid estimate of iron in the SN only. The third study investigated whole brain white matter microstructural integrity in A53T mice using the MRI technique, diffusion tensor imaging (DTI). A53T mice at 5 to 9 months exhibited altered microstructural integrity compared to wildtypes, in alignment with existing literature of abnormal alpha-synuclein models. This thesis improves upon the characterisation of genetic mouse models of PD on translatable biomarkers of early pathology. Clarifying these biomarker changes in animal models of PD will facilitate further research to investigate the underlying pathomechanisms specific to PD.
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ItemPreclinical and clinical investigation of potential pharmacotherapies for disordered overeating( 2023-12)Disordered overeating is a transdiagnostic feature of several eating disorders and obesity. Both individuals with binge eating and certain types of obesity often exhibit compulsive eating behaviour characterised by a sense of loss of control. The foods eaten during these episodes are typically those high in fat and sugar i.e. highly palatable, calorically dense foods. Chronic overconsumption of these foods can lead to deleterious health consequences. As such, compulsive eating is often associated with significant comorbidities. Given the clinical consequences and impact on health, disordered overeating needs to be addressed adequately. Unfortunately, to date, there is a lack of effective treatments for disordered overeating. This, in part, is likely due to the lack of understanding of the aetiology and the biological mechanisms underlying this behaviour. Emerging evidence has shown similarities between disordered overeating and addiction, including clinical similarities in so much that the behaviour persists despite negative consequences, as well as similarities in the neurobiology. Moreover, highly palatable foods have been shown to act in the brain in a way that is “drug-like” in nature. Thus, addiction neuroscience therapeutics may represent a new area of research for the development of treatment for disordered overeating. Both glutamate and hypothalamic neuropeptides such as orexin have been shown to play a role in mediating the actions of drugs of abuse in animal models of drug addiction, as well as a role in hedonic eating. As such, glutamate and hypothalamic neuropeptidess represent an appealing area of research for the development of pharmacotherapies for disordered overeating. Therefore, this thesis aimed to investigate potential pharmacotherapies for disordered overeating that focused on these two systems. In this thesis, I used both preclinical and clinical approaches to address this aim. In the preclinical study, I evaluated the involvement of lateral hypothalamic neuropeptides including orexin, melanin-concentrating hormone (MCH) and cocaine- and amphetamine- regulated transcript (CART) in a mouse model of stress induced-binge eating. I found that orexin neurons, but not MCH and CART neurons, are activated in response to stress-induced binge eating. I confirmed previous knowledge about the role of orexin in hedonic overeating and extended the findings that orexin mediates binge eating behaviour induced by repeated mild stress in ad libitum fed animals. Further, I showed that a selective orexin 1 receptor antagonist, SB-334867, significantly reduced the stress-induced binge eating without altering locomotor activity. SB-334867 treatment altered neural activation in the nucleus accumbens core and lateral bed nucleus of stria terminalis suggesting that these brain areas may be involved in the neurocircuitry of orexin-mediated stress-induced binge eating. In the clinical study, I examined the feasibility and preliminary efficacy of N-acetylcysteine (NAC), a compound that targets glutamate homeostasis, for loss of control eating. I found that delivering a 12-week NAC intervention is feasible and safe. I also found that NAC treatment reduces loss of control eating. This preliminary finding provides a basis for further investigation on the efficacy of NAC treatment for compulsive eating using a larger scale RCT. Collectively, I have provided evidence for the potential use of an orexin receptor antagonist and NAC for the treatment of disordered overeating.
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ItemMass Spectrometry As A Tool For Drug Development In SCN2A Developmental and Epileptic Encephalopathies( 2023-11)Mutations within the SCN2A are recognized as a prominent cause of autism spectrum disorder and a spectrum of developmental and epileptic encephalopathies (DEEs). As more patients are affected by mutations in SCN2A, it drives the need for precision medicines and to better understand the biology and pathogenesis of the disorder. The SCN2A gene encodes the voltage-gated sodium channel, Nav1.2. Antisense oligonucleotides (ASOs) are a class of drugs being developed to treat SCN2A disorders by knocking down SCN2A mRNA and therefore protein levels. In this study, targeted mass spectrometry methods are utilised to measure Nav1.2 protein levels directly and untargeted, or “discovery”, proteomic methods are used to measure the entire proteome in brain tissue collected from various SCN2A mouse models and mice treated with an experimental ASO therapy. Three SCN2A knock-in missense mutation mouse models are included in the study, each representing a phenotypic group within the SCN2A disease population. These results all support that the ASO has strong target engagement on the protein expression similar to mRNA level. The mutant mouse models are R1882Q representing the early seizure onset phenotype, R853Q representing the late seizure onset phenotype, and S1758R representing the autism with no seizure phenotype. When measuring Nav1.2 in R1882Q mouse whole-brain treated with an ED80 dose (80% knockdown Scn2a mRNA) of an Scn2a-targeting ASO, Nav1.2 was reduced 72% compared to R1882Q mice treated with a scrambled-control ASO. WT mice treated with an ED50 dose of SCN2A-targeting ASO at P30 (post-natal day 30) with brain tissue collected over a 5-week period showed consistent knockdown of Nav1.2 protein of approximately 50% 2- and 3-weeks post-injection in cerebellum, hippocampus, and cerebellum. In the mutant models of Scn2a encephalopathy, Nav1.2 expression remained unchanged in R1882Q and R853Q mutant mice compared to WT littermates while Nav1.2 expression was reduced ~50% in S1758R mutant mice compared to WT littermates, suggesting haploinsufficiency may be a major driver of the autism phenotype. Global proteomic analysis revealed several potential off-target and/or toxicity biomarkers of ASO treatment. These biomarkers were primarily associated with neuroinflammation, including neurofilament heavy (Nefh) and programmed cell death 5 (Pdcd5). Global proteomic analysis in the 3 mutant models showed unique proteomic profiles in each, with minimal overlap, suggesting the very different phenotypes also lead to differences in protein expression and dysregulation. However, dysregulated proteins across the 3 models were involved in several shared pathways, including those responsible for regulation of synaptic signalling and mitochondrial function and metabolism. The exploration of novel epileptic mouse models and mice treated with experimental antisense oligonucleotides through proteomic analysis has unveiled promising prospects for potential new biomarkers. This integrated approach has provided invaluable insights. It is anticipated that certain biomarkers identified may undergo further validation and potentially be employed in clinical trials for emerging SCN2A drugs. These biomarkers could serve to monitor disease progression and assess the effectiveness of innovative treatments, building upon prior research efforts.
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ItemSearch for genomic, molecular, and cellular biomarkers for the early diagnosis of Alzheimer's disease( 2023-12)Alzheimer’s disease (AD) is a chronic neurodegenerative disease defined by either postmortem pathologies or in vivo by AD specific neuroimaging and biofluid biomarkers. Late onset AD (LOAD) is a continuum that includes a preclinical stage, a long silent period from the first evidence of beta amyloid (Abeta) accumulation to the first clinical symptom (learning deficits), a prodromal stage, and the late dementia stage. In the last two decades, AD genomic studies have extensively implicated the role of Abeta clearance associated innate immune pathways in LOAD. Given the crosstalk between the central and peripheral pools of Abeta clearance, the research question of this thesis is to develop blood based biomarkers, particularly in myeloid cells, to meet the urgent need for minimally invasive, cost effective screening of preclinical AD at population level. This study has delved into somatic mosaicism of peripheral intermediate monocytes via novel fluorescence activated cell sorting (FACS) of single cells and whole genome sequencing (scWGS). A total of 17 AD associated single nucleotide polymorphisms (SNP) and insertions and deletions (INDEL) were identified in novel loci, including the DR51 region, ADAMTS20, MAP4, CLEC18A, and ZNF regions. Two genomic biomarker panels were constructed, illustrating superior performance in predicting individuals with Abeta load with an area under curve (AUC) over 0.98. These AD associated somatic mutations were enriched in regulatory regions, implying that they may perturbate the expression of myeloid specific AD associated genes to interfere Abeta clearance. This study was the first attempt to characterise the somatic mosaicism of peripheral myeloid cells in AD using unbiased scWGS. To explore the molecular and cellular biomarkers linked to peripheral myeloid cells, this thesis also screened three sets of innate immune markers, selected from AD genomic studies and immunologic studies, using flow cytometry immunophenotyping. The surface expressions of P2X7, CD11b, and CD11c on peripheral monocytes were found to be reduced at the preclinical stage and remained low throughout the disease course, consistent with alterations of Abeta clearance pathways in the early stage of AD. Building upon this insight, this thesis developed an Abeta clearance-associated, blood-based biomarker panels, CD11c, CD59, CD163, and CD91 expression on leukocyte surface, to classify individuals with Abeta load with an AUC ranging from 0.87 to 0.88. Another five immunoreceptor biomarker panel, CCR2, CX3CR1, CR1, P2X7 (or RAGE), and PILRA (or AXL) expression on leukocyte surface, was also identified. This panel classified individuals with Abeta load with an AUC ranging from 0.89 to 0.923. This study identified the elevated CCR2, CX3CR1, CR1, P2X7, CD163, CD59, and the reduced PILRA expression on the surface of peripheral leukocytes among preclinical AD patients, also consistent with early alterations of Abeta clearance pathways during the progression of AD. Overall, this thesis has translated AD genomic knowledge into diagnostic tools and developed a series of novel blood based biomarker panels to facilitate the early diagnosis of AD. All composite panels have illustrated promising performance in identifying individuals with an increased Abeta burden in the brain. This thesis recognises the intriguing discrepancies between the central and peripheral compartments, casting additional light into the role of Abeta clearance associated innate immunity in the pathogenesis of AD. We hope that the proposed biomarker panel will make contributions to the screening, diagnosis, and monitoring of AD in the clinic.
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ItemThe influence of cocaine on cortical neurons( 2023-11)Cocaine is a powerfully addictive stimulant drug which produces short-term euphoria in users by highjacking the brain’s reward system. By binding to synaptic transporters, cocaine prevents the removal of specific neuromodulators, such as dopamine, serotonin and noradrenaline from the synaptic cleft. This leads to elevated extracellular levels of these neuromodulators which leads to re-activation of the synapse and neuronal hyper-excitability. Despite the prevalence and dramatic effects of cocaine use, the functional effects of cocaine exposure on the activity of neurons in the intact brain are poorly understood. To fill this gap in knowledge, my Ph.D research investigated the influence of cocaine on neural activity, presented in this Thesis as two projects. First, I investigated how cocaine influences the processing of information within the sensory cortex. Using voltage recordings and two-photon dendritic and somatic Ca2+ imaging in vivo, I measured the influence of acute exposure of cocaine on layer 2/3 (L2/3) pyramidal neurons within the primary somatosensory cortex (S1). Here, cocaine dampened membrane potential state transitions and decreased spontaneous somatic action potentials. In contrast to the uniform decrease in background spontaneous activity, cocaine had a heterogenous influence on sensory encoding, increasing tactile-evoked responses in dendrites which did not typically encode sensory information, and decreasing those dendrites which were more reliable sensory-encoders. Combined, these findings illustrate that exposure to cocaine has a heterogenous influence on cortical neurons, leading to the dampening of background spontaneous activity and selective filtering of sensory input. Second, I investigated how cocaine influences the activity of thalamic axonal projections, and the influence this has on cortical neurons in a different context. The thalamus acts as a central hub and is perfectly positioned to drive the modulation of cortical activity following cocaine exposure. Two photon calcium imaging was performed in both the higher-order (POm) thalamic axonal projections and layer 2/3 (L2/3) pyramidal neurons within the primary somatosensory cortex (S1) of awake mice during cocaine administration. Single exposure to cocaine caused a significant increase in the thalamic and cortical signaling in S1, and chemogenetic dampening of POm suggested the thalamus may predominantly drive the increase in cortical activity during acute cocaine. Combined, the results of these studies will provide invaluable insight into the effects of cocaine on brain functioning and will help us unravel the neural correlates of drug addiction.
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ItemRegulation of Ferroptosis Signalling Pathways: Implications for Alzheimer's Disease( 2023-12)Background and aims: The natural history of Alzheimer's disease (AD) involves the formation of extracellular amyloid plaques followed by intracellular neurofibrillary tangles that are associated with neurodegeneration, leading to cognitive deterioration and death. The mechanism of neurodegeneration in AD is not fully understood. Ferroptosis is a form of regulated cell death due to uncontrolled phospholipid peroxidation, which has been implicated as a mechanism of neurodegeneration in AD. Amyloid precursor protein (APP) has been considered the central protein involved in the pathogenesis of AD. Amyloidogenic processing of APP via beta-secretase (BACE-1) followed by gamma-secretase generates amyloid-beta peptides, the major component of amyloid-beta plaques. Alternatively, non-amyloidogenic APP processing via alpha-secretase generates soluble amyloid precursor protein alpha (sAPPalpha) that protects against rotenone-induced toxicological insults, serum deprivation and hypoxia. The role of APP and its processing and APP-associated signalling in ferroptosis has yet to be investigated. The first part of my thesis project examined the impact of APP and its processing on ferroptosis. Growing evidence suggests that vitamin A (retinol) and its metabolite all-trans retinoic acid are modulators of APP processing and neuroprotectors in pre-clinical and clinical AD models. The second aim of the project was to examine whether retinol and its metabolites affect ferroptosis sensitivity. Brain-derived neurotrophic factor-tyrosine kinase B receptor (BDNF/TrkB) signalling has also been shown to modulate APP processing and protect against neurodegeneration in pre-clinical and clinical AD models. The final aim of the project was to characterise the role of BDNF/TrkB signalling on ferroptosis. Methods: We used a cell culture model of ferroptosis to investigate these thesis projects. Several inducers were used to cause ferroptosis in diverse neuronal and non-neuronal cell lines. This thesis used various molecular biology, biochemical and cell-free techniques to investigate ferroptosis regulation. Results: The first aim of the thesis found that neuronal and non-neuronal cell lines expressing APP desensitise ferroptosis. APP expression enhanced the heme-Nrf2-GPX4 axis, the central cellular antioxidant defence, which explains APP desensitisation of ferroptosis. By investigating the role of APP processing on ferroptosis, we found that inhibiting alpha-secretase sensitises cells to ferroptosis, possibly via downregulating GPX4. However, we did not observe the involvement of APP-processed products in the pro-ferroptotic effect of alpha-secretase inhibition. By investigating the second aim, we showed retinol and its major metabolites, all-trans-retinal and all-trans-retinoic acid, confer superior anti-ferroptotic activity than alpha-tocopherol (an endogenous anti-ferroptotic vitamin), most likely acting as radical trapping antioxidant (RTA) agents, not by interfering with APP processing. Conversely, anhydroretinol (an antagonist of retinol uptake and functions) sensitised ferroptosis, suggesting a role for retinol signalling against ferroptosis at physiological levels. The final part of the thesis showed the role of several TrkB modulators on ferroptotic susceptibility. The modulators of the TrkB receptor, including an agonist, antagonist and inhibitor, were found not to affect RSL3-induced ferroptosis via modulating the TrkB receptor signalling, suggesting that TrkB modulation might not directly involve ferroptosis in our model. In contrast, several modulators of the TrkB receptor conferred anti-ferroptotic activity, which may be explained by their inherent RTA properties. Conclusion: The thesis identified several novel regulatory pathways involving ferroptosis and neurodegeneration that could be targeted for AD therapy.
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ItemInvestigating the circuit mechanisms of the Solitary Tract Nucleus( 2023-10)Maintaining physiological homeostasis requires the brain to accurately receive and process information on the state of the body. Interoception, the sense of the internal state of the body, is a fundamental component of homeostasis that links the body’s physiological needs with both conscious, and unconscious, feelings and behaviour. Understanding how the brain makes sense of the internal state of the body is a major challenge due to the enormous diversity of sensory modalities. To determine the neural basis of interoception, we must first define the features of the circuit mechanisms by which sensory signals are processed and integrated in the maintenance of homeostasis. The solitary tract nucleus (NTS) is the initial site for central processing of sensory information relating to the internal state of the body. A highly heterogeneous nucleus, the cellular and circuit mechanisms of sensory processing at this initial site are not well defined. In this thesis, I aimed to first classify the electrophysiological features – groups of distinct electrophysiological characteristics, that define groups of NTS neurons. I then went on to investigate plasticity of these features via a perturbation of the vagus nerve, the major source of afferent sensory input to the NTS. I developed a semi-supervised machine learning method to define groups of neurons with electrophysiological characteristics that did not correlate with homogeneous neurochemistry. Following chronic vagus nerve stimulation (VNS) in Sprague-Dawley rats, active firing patterns of NTS neurons were shifted from irregular burst firing, towards tonic firing, identified via a multimodal analysis of electrophysiological characteristics. Plasticity was also identified in NTS neurons following chronic VNS in a rodent model of genetic absence epilepsy, however the effect was not sufficient to reduce hyperexcitability of neurons to a non-pathological control. Throughout this thesis, I present a case for investigating neural mechanisms through the lens of homeostasis, whereby multimodal features, not individual characteristics, define classification of neurons and their function within circuitry.
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ItemMimicking the effects of gene x environment interaction with small non-coding RNAs associated with anxiety and depression( 2023-06)Depression and anxiety are debilitating psychiatric disorders, which significantly depend on genetic predisposition and changing environments. One in three patients is resistant to current antidepressant treatment, highlighting the need for novel therapeutics to improve patient outcomes. Understanding how combination of genetic and environmental factors contribute to the development of depression and anxiety through microRNAs will aid the development of novel therapeutics for affective disorders. During my PhD, I explored how combinations of genetic and environmental factors affect expression of brain miRNAs in a mouse model of treatment-resistant depression (TRD). In the first part of my PhD project, I described miRNA composition in the hippocampus of the serotonin transporter knock-out (5-HTT KO) mice compared to wild-type mice in standard housing conditions. 5-HTT KO mice have increased depression-like behaviour and do not respond to classic antidepressant treatment, which make them a good model of TRD. This is the first study describing miRNA profiles in the brain tissues of a mouse model of TRD. We discovered novel miRNAs, which could be used as markers of TRD. The enrichment analysis of target genes of these miRNAs revealed pathways relevant to stress response, highlighting the importance of changing environments in the development of TRD. Next, I described miRNA profiles in 5-HTT KO mice after stress and exercise, which was the first study on how gene x environment interactions affect miRNA composition in the brain of mice genetically predisposed to TRD. Based on these data, I targeted several miRNAs using novel approaches of miRNA modulation to mimic beneficial effects of exercise and stress-reduction to develop new treatment for TRD. I observed a significant antidepressant-like effect after treatment with miRNA mimic, which proved that miRNAs can not only be a marker of depression but are themselves targets for the treatment of depression. The follow-up bioinformatic analysis revealed that miRNA mimic treatment enhanced neuroplasticity and neurotrophic support by activating cascade of genes, which protect or rescue neurons that are vulnerable after stress or other insults. This study provided the first description of miRNA alteration in a mouse model with serotonergic dysfunction and highlighted the potential of these miRNAs as therapeutic targets for TRD. These results provide further evidence to highlight the importance of considering gene-environment interactions in the management and treatment of affective disorders. Ultimately, these findings will aid in the development of genetically-informed precision medicine for serotonergically-dependent refractory mental illness.
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ItemInterrogating TAM receptor activation for therapeutic benefit in multiple sclerosis( 2023-05)Multiple sclerosis is an autoimmune neurodegenerative disease characterized by demyelination and axonal damage in the central nervous system (CNS). Remyelination plays a crucial role in axonal protection and functional recovery. The GAS6 protein has emerged as a promising candidate for enhancing remyelination. This thesis aims to uncover the underlying mechanisms through which GAS6 exerts its pro-myelinating effect. Additionally, it delves into the pharmacokinetic properties of this protein, emphasizing the significance of gamma-carboxylation in the GAS6 GLA domain in mediating myelination in vitro, along with its residence time in the CNS. The latter part of this doctoral work demonstrates the utilization of the PEGylation approach to extend the brief CNS residence time of the GAS6 protein. The data from this project suggest that the Tyro3 receptor significantly contributes to GAS6's pro-myelinating effect in the CNS after demyelination. This observation appears to be partly driven by mature oligodendrocytes and seems largely independent of the inflammatory response. This research also underscores the importance of gamma-carboxylation within the GAS6 GLA domain for its pro-myelinating effect in vitro. Additionally, it reveals that GAS6 exhibits a short residence time of less than two hours in the murine brain. Using the PEGylation approach, a bioactive variant of this protein with an extended CNS residence time was successfully generated. In summary, this work identifies the Tyro3 receptor as a potential target for the GAS6 pro-myelinating effect and sheds light on some pharmacokinetic properties of the GAS6 protein, particularly highlighting the significance of its post-translational modifications and brief CNS residence time.
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ItemSperm noncoding RNAs as mediators of paternal epigenetic inheritance modulating offspring affective and social behaviours( 2023-06)Background: Studies have shown that paternal environmental conditions prior to conception can influence the innate behaviours of their offspring, and the evolutionary impacts of such intergenerational effects are therefore of considerable interest. Epigenetic mechanisms have been shown to underlie this inheritance, as the microinjection of sperm small noncoding RNAs into fertilised oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. Our group previously showed in a mouse model of daily stress that glucocorticoid treatment of adult male breeders prior to conception leads to increased anxiety-related behaviours in male offspring, and this accompanies changes in the paternal sperm small noncoding RNA profile. Additionally, in a model of paternal running wheel voluntary exercise preconception, our group observed lower anxiety levels and a more robust fear extinction memory in the male offspring, as well as changes in paternal sperm small noncoding RNA expression. Aims: In this study, we aimed to understand the transgenerational effects of paternal stress exposure on the social behaviour of the male progeny and its potential influence on reproductive success by analysing its effects on social reward, male attractiveness and social dominance. We also assessed the paternal sperm long noncoding RNA profile following glucocorticoid treatment or running wheel voluntary exercise. We used CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. We next sought to determine the role of sperm long noncoding RNAs by microinjecting them into fertilised oocytes. Results: We report that paternal corticosterone-treatment was associated with increased display of subordination towards other male mice. Those mice were unexpectedly more attractive to female mice while expressing reduced levels of the key rodent pheromone Darcin, contrary to its conventional role in driving female attraction. Furthermore, no overt differences of the prefrontal cortex transcriptome were found in the offspring, implying that peripheral mechanisms are likely contributing to the phenotypic differences. No transgenerational differences were observed. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable elements. Although they have poor functional annotation, bioinformatic approaches indicated their expression in the brain, as well as their potential in regulating brain function. Running wheel exercise led to hundreds of downregulated lncRNAs, as well as transposable elements, and bioinformatic strategies predicted their function in biological processes, such as cell adhesion. Lastly, we separated and isolated the sperm long noncoding RNA population after glucocorticoid exposure and performed microinjections into fertilised oocytes. We observed that the resulting adult offspring had lower body weight and altered behavioural responses in the light-dark box and Porsolt swim test. Conclusion: Our findings highlight the potential of paternal stress to affect intergenerational (mal)adaptive responses. They also provide insights into the potential biology of long noncoding RNAs and highlight that efforts to annotate their function are highly necessary for the understanding of the mechanisms underlying the epigenetic inheritance. We are also the first to show that voluntary exercise modulates sperm long noncoding RNAs expression.