Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.

The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.

Running from depression: the antidepressant-like potential of prenatal and pre-pubertal exercise in adolescent FSL rats exposed to an early-life stressor.

OBJECTIVE: We aimed to answer the questions of whether early-life (perinatal and/or juvenile) exercise can induce antidepressant-like effects in a validated rodent model of depression, and whether such early-life intervention could prevent or reverse the adverse effects of early-life stress in their offspring. METHODS: Male and female Flinders sensitive line rats born to a dam that exercised during gestation, or not, were either maternally separated between PND02 and 16 and weaned on PND17 or not. Half of these animals then underwent a fourteen-day low-intensity exercise regimen from PND22. Baseline depressive-like behaviour was assessed on PND21 and then reassessed on PND36, whereafter hippocampal monoamine levels, redox state markers and metabolic markers relevant to mitochondrial function were measured. RESULTS: Pre-pubertal exercise was identified as the largest contributing factor to the observed effects, where it decreased immobility time in the FST by 6%, increased time spent in the open arms of the EPM by 9%. Hippocampal serotonin and norepinephrine levels were also increased by 35% and 26%, respectively, whilst nicotinic acid was significantly decreased. CONCLUSION: These findings suggest that pre-pubertal low-intensity exercise induces beneficial biological alterations that could translate into antidepressant behaviour in genetically susceptible individuals.

Genetically predisposed and resilient animal models of depression reveal divergent responses to early-life adversity.

OBJECTIVE: Early-life adversity (ELA) is one of the strongest predictors of childhood depression that may be exacerbated by a genetic predisposition to develop depression. We therefore investigated the bio-behavioural effects of an early-life stressor in an accepted rodent model of depression. METHODS: The Flinders sensitive line (FSL) and resistant line (FRL) rats were subjected to an early-life stressor, whereafter their bio-behavioural response during pubertal onset was evaluated. Male and female pups were maternally separated for 3 h per day from postnatal day 02 (PND02) to 17, when they were also weaned. Control animals were left undisturbed, until weaning on PND21. Depressive-like behaviour was analysed on PND21 and reassessed on PND36. Hippocampal monoamine levels, markers of oxidative stress and metabolic markers implicating mitochondrial function were also measured. RESULTS: On PND21, the non-maternal separation and early weaning (non-MSEW) FSL rats spent 10% more time mobile than their FRL controls in the tail suspension test (TST) yet displayed increased depressive-like behaviour in the forced swim test (FST) on PND36. This depressive-like behaviour coincided with increased hippocampal norepinephrine levels, serotonin turnover and a dysfunctional redox state. Maternal separation and early weaning (MSEW) appeared to initially reduce early-life (PND21) depressive-like behaviour in the TST but then induced depressive-like behaviour on PND36 and increased norepinephrine levels more profoundly in the FRL rats. CONCLUSION: These findings highlight the need to further investigate the stress response pathway in these animals and that the absence or presence of genetic susceptibility may influence the presentation of ELA effects.

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Increased depressive-like behaviour of postpartum Flinders sensitive and resistant line rats is reversed by a predictable postpartum stressor.

During the peripartum period, women are at an increased risk to develop perinatal distress, presenting as symptoms of depression and/or anxiety. Yet, due to practical and ethical restrictions, our understanding of this condition remains limited. Animal studies that focus on the neuropsychiatric mechanisms associated with the postpartum period, often ignore the genetical predisposition factor. We therefore investigated whether pregnancy could alter the bio-behavioural profile of the Flinders sensitive and resistant line rats, and whether these effects are exacerbated by a postpartum stressor. Postpartum dams were compared to nulliparous controls in behavioural tests, analysing depressive- and anxiety-like behaviours. Next, postpartum dams were subjected to a maternal separation and early weaning (MSEW) regimen, with their behaviour and serotonergic and noradrenergic concentrations compared to rats not separated from their pups. Regardless of strain, pregnancy decreased time spent in the open arms of the elevated plus maze and hippocampal serotonin concentrations. Time spent immobile in the forced swim test was also increased, with a significant effect in the FRL and a strong trend in the FSL rats. MSEW reversed these behaviours in both strains and increased social interaction with a male counterpart in the FSL rats, without influencing hippocampal or cortical serotonin or norepinephrine. Taken together, these results suggest that pregnancy influences postpartum behaviour, in a strain-dependent manner. Contrary to what we expected, MSEW overall decreased depressive- and anxiety-like behaviours, with strain specific differences, indicating that a chronic, predictable stressor may not necessarily adversely affect postpartum behaviour.

Reviewing the mitochondrial dysfunction paradigm in rodent models as platforms for neuropsychiatric disease research.

Neuropsychiatric disorders have complex pathophysiological constructs, requiring translational models to improve our understanding thereof. Mitochondrial dysfunction, generally associated with neurodegenerative disorders, is gaining interest as a key factor in the etiology of psychiatric conditions because of the often comorbid psychiatric symptoms observed. Although translational models of psychiatric disorders, support mitochondrial involvement, these models do not have a dysfunctional bio-energetic system as primary construct. Here, we consider the construct, face, and predictive validity of mitochondrial models from a neuropsychiatric perspective, to identify novel animal models that can improve our understanding of the underlying bio-energetic mechanisms of these conditions and treatments.

An acute dose-ranging evaluation of the antidepressant properties of Sceletium tortuosum (Zembrin®) versus escitalopram in the Flinders Sensitive Line rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. AIM OF THE STUDY: To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. MATERIALS AND METHODS: The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. RESULTS: Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. CONCLUSIONS: Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST, as assessed in FSL rats. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.

Stereotypy and spontaneous alternation in deer mice and its response to anti-adenosinergic intervention.

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20 mg kg-1  day-1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.

The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment.

The recent outbreak of the corona virus disease (COVID-19) has had major global impact. The relationship between severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection and psychiatric diseases is of great concern, with an evident link between corona virus infections and various central and peripheral nervous system manifestations. Unmitigated neuro-inflammation has been noted to underlie not only the severe respiratory complications of the disease but is also present in a range of neuro-psychiatric illnesses. Several neurological and psychiatric disorders are characterized by immune-inflammatory states, while treatments for these disorders have distinct anti-inflammatory properties and effects. With inflammation being a common contributing factor in SARS-CoV-2, as well as psychiatric disorders, treatment of either condition may affect disease progression of the other or alter response to pharmacological treatment. In this review, we elucidate how viral infections could affect pre-existing psychiatric conditions and how pharmacological treatments of these conditions may affect overall progress and outcome in the treatment of SARS-CoV-2. We address whether any treatment-induced benefits and potential adverse effects may ultimately affect the overall treatment approach, considering the underlying dysregulated neuro-inflammatory processes and potential drug interactions. Finally, we suggest adjunctive treatment options for SARS-CoV-2-associated neuro-psychiatric symptoms.

Pre-pubertal, low-intensity exercise does not require concomitant venlafaxine to induce robust, late-life antidepressant effects in Flinders sensitive line rats.

A significant number of adolescents are considered insufficiently active. This is of concern considering the negative association between physical activity and major depressive disorder (MDD). There is a lack of approved pharmacological treatment options in this population partly due to limited information on the risks associated with lasting effects during early life. Therefore, interest in non-pharmacological strategies is gaining popularity with low- to moderate-intensity exercise being especially attractive for its antidepressant-like effects and augmentation properties in combination with antidepressants. Early-life development might present a unique "window of opportunity" to induce long-term beneficial effects in individuals treated with central acting drugs, such as antidepressants. Therefore, we investigated the bio-behavioural effects of pre-pubertal, low-intensity exercise (EXE) and/or venlafaxine (VEN) on depressive-like behaviour in juvenile (postnatal day 35 (PND35)) and young adult (PND60) stress-sensitive Flinders sensitive line (FSL) rats. Interventions were introduced during pre-pubertal development, that is PND21-34, followed by a 26-day washout/sedentary period, when bio-behavioural analyses were performed in the early adulthood group. VEN, alone or in combination with EXE, proved ineffective in inducing any bio-behavioural changes in either age group. EXE did not induce early-life antidepressant-like effects, despite increasing frontal serotonin (5-HT) and noradrenaline (NA) levels. Later in life (PND60), pre-pubertal exercise reduced immobility and increased coping behaviours, together with increased cortical 5-HT levels, despite a significant reduction in locomotor activity. These findings emphasize a strong serotonergic basis to the observed delayed antidepressant effects of EXE later in life.