1. Introduction
Normal mitochondrial function is a pivotal player in maintaining the cellular physiological state through mechanisms such as providing energy and buffering cytosolic Ca2+ concentration (Rizzuto et al., 2012). Many biochemical reactions depend on or can be modulated by the levels of cellular adenosine triphosphate (ATP) and Ca2+. Therefore, the mitochondrial function is a hub that indirectly sends modulatory signals to the cellular machinery. The importance of mitochondria in neurons is even more prominent because of their high energy demands (Hyder et al., 2013). Mitochondrial failure in neurons can affect their excitability, neurotransmitter release, and viability (Kann & Kovacs, 2007).
In several medical settings, the main challenge is decreased mitochondrial function in neurons. It may be acute and have an extrinsic origin, like when the oxygen and or glucose supply is disturbed in the brain (e.g. ischemic and hemorrhagic stroke, perinatal hypoxia, and prolonged cardiopulmonary resuscitation), or may be chronic and intrinsic, like when the mitochondrial energetic capacity of neurons is reduced (e.g. aging and neurodegenerative diseases). These functional losses decrease the level of available ATP, increase reactive oxygen species, and disturb Ca2+ hemostasis (Yin et al., 2014). The consequences of these turbulent events in the brain can be observed at the cellular and behavioral levels.
One of the obvious features that can be significantly influenced by altered mitochondrial function is behavioral change (social or non-social type). Significantly altered behaviors have been reported in several models with impaired mitochondrial function (Kupsch et al., 2014; Pacelli et al., 2010; Watson et al., 2014). One model characterized by impaired mitochondrial function is the 3-nitropropionic acid (3-NP) model, which is widely used to imitate Huntington disease (HD) symptoms (Borlongan et al., 1997). Although several studies have investigated different behavioral changes, including altered locomotor activity and memory, in the context of 3-NP exposure (Dhir et al., 2008; Jain & Gangshettiwar, 2014; Kumar et al., 2010; Thangarajan et al., 2014), evaluation of social interaction and other non-social behaviors is quite limited.

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is a modulator of behavior (Iniguez et al., 2014; Packard et al., 2016). For example, overactivity of the HPA axis has adverse behavioral consequences like anxiety (Faravelli et al., 2012), depression (Pariante & Lightman, 2008), and impaired social behaviors (Bagosi et al., 2017). The brain’s glucocorticoid receptor (GR) participates in the feedback loop and controls HPA axis activity. Alongside GR, FK506 binding protein 5 (FKBP5) is a cellular protein that modulates GR function (Zannas et al., 2016). Despite these roles, how these proteins respond to mitochondrial failure and complex II inhibition, in particular, is unclear. Measuring the content of mitochondrial cytochrome may also help to better understand the processes after complex II inhibition in the electron transport chain.
Monoamine oxidase (MAO) enzymatic activity is another possible agent that can have significant impacts on controlling behavior and contribute to the pathogenesis of a wide range of mental disorders and neurodegenerative diseases, from antisocial personality disorder to Parkinson’s disease (Bortolato & Shih, 2011). Socio-behavioral disorders due to the disruption of mitochondrial processes can be related to altering MAO activity (Bortolato et al., 2013). 
The current study investigated whether mitochondrial complex II inhibition influences social or non-social behaviors. To better understand the underlying mechanisms, we measured the levels of GR, FKBP5 protein, cytochrome contents, and MAO A and B (MAO-A and MAO-B) activities in the striatum (ST), hippocampus (HIP), and prefrontal cortex (PFC) of rats after 3-NP treatment. The findings of this study suggest a relationship between mitochondria and social behavior.
2. Materials and Methods
Study animals
Adult male Wistar rats (220-240 g) were obtained from the Laboratory Animal Center of Pasteur Institute, Tehran, Iran. Rats were kept under controlled environmental conditions of constant temperature (23±2 °C) and a 12 h light/12 h dark cycle. The animals had access to food and water ad libitum. 
Drug administration
The animals were divided into two groups: Control (which received the vehicle daily) and treatment. 3-NP (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in saline. The rats in the treated group received 3-NP treatment (20 mg/kg/d, intraperitoneally [IP]) for five consecutive days (n=8-10/group), as it was approved for the HD model.
Behavioral tests
Before conducting the social interaction test, the animals were habituated in a row in an open field arena (OF). On the test day, the rats were separately segregated into small cages in the test room for three hours. After that, two unfamiliar rats were placed in opposite corners of the OF arena, and their activities were videotaped for 10 minutes. The test was recorded using a video camera suspended 2 m above the testing apparatus. Immediately after behavioral testing, the animals were returned to their cages, and OF was wiped entirely with 70% ethanol and tissue paper to reduce any lingering olfactory cues.
The observed behaviors were divided into the following two categories. Social behaviors include social nose contact (advertent nose-to-body contact with the other rodent), genital investigation (sniffing or assessing the anogenital region), and play behaviors (chasing the other rodent within a tail length distance), wrestling (harsh and tumble play) and pouncing (one rodent nosing or rubbing the nape of the other one) (Mikulecká et al., 2014). Non-social behaviors include (Manfré et al., 2018) exploring (walking around the field and sniffing the walls and floor), self-grooming (any grooming behavior that a rodent performs in a normal sequential pattern to clean its own body and fur) (Silverman et al., 2010), rearing (the total time that the rodent temporarily stands on its hind legs with the intention exploring) (Valvassori et al., 2017), solitary behavior (activities that are not aimed toward another rat), and immobility (del Angel Ortiz et al., 2016; Lorbach et al., 2018). Behaviors were blindly scored and assessed by two independent observers for each animal. The time spent by two rats engaging in social behaviors, including play behavior, genital investigation, and social nose contact, was also calculated to assess their total social behavior (Lech et al., 2021).
Tissue preparation
After assessment of behavioral tests, rats were euthanized by CO2 asphyxiation and decapitated. The brains were removed, ST, HIP, and PFC were dissected on ice, frozen in liquid nitrogen, and then stored at -80 °C for further molecular analysis.

Western blotting 
Different dissected brain regions (ST, HIP, and PFC), based on the Paxinos and Watson’s stereotaxic atlas, were homogenized in a lysis buffer (Roche, Penzberg, Germany). The Bradford colorimetric method was used to determine protein concentration (Bradford, 1976). Sixty micrograms of total protein were loaded on sodium dodecyl sulfate (SDS)-polyacrylamide gels and were separated by electrophoresis. Proteins were electrotransferred onto polyvinylidene difluoride (PVDF) membranes. Membranes were blocked and incubated with primary antibody overnight at 4 °C and then with secondary antibody for 90 minutes. Immunoreactive polypeptides were revealed by enhanced chemiluminescence reagents. The protein bands were analyzed by ImageJ software and normalized to β-actin as a housekeeping protein. We used the primary, including GR, FKBP5, and β-actin (1:1000, Cell Signaling Technology, Beverly, MA, USA) and secondary HRP-conjugated anti-rabbit antibodies ‎(1:3000, Cell Signaling Technology, Beverly, MA, USA)‎.
Cytochrome measurements
Williams’s method (1964) was applied to determine the content of various cytochromes in isolated mitochondria (Clark & Nicklas, 1970). A double-beam scanning spectrophotometer was used to get the cytochrome spectra of the mitochondria. Small amounts of sodium dithionate and hydrogen peroxide were added to obtain the reduced minus-oxidized spectra (Jones & Poole, 1985; Kumar et al., 2008; Mehrotra et al., 2015).
MAO-A and MAO-B activities
To estimate MAO-A activity, the sample was mixed with a buffer containing sodium phosphate buffer and 5-hydroxytryptamine (4 mM). The change in absorbance was recorded at a wavelength of 280 nm against the blank. The sample was mixed with sodium phosphate buffer and benzylamine (100 mM) to estimate the MAO-B activity. Then, absorbance was recorded at a wavelength of 249.5 nm against the blank (Dhingra & Goyal, 2008; Saleem et al., 2023).
Data analysis
All the results were expressed as Mean±SEM. The normal distribution of data was checked using the Kolmogorov–Smirnov test. The data were analyzed using an unpaired t-test. The statistical analyses were performed using GraphPad Prism software, version 9.5.1 (San Diego, CA, USA). Statistical significance was accepted at P<0.05.
3. Results
Social interaction test analysis
Social behaviors
The behavioral test yielded that 3-NP-injected rats had a significantly lower duration of play behavior (Figure 1A) and genital investigation (Figure 1B) than those in the control group with the Mean±SEM of 12.37±0.46 vs 26.87±2.70 s for play behavior (P=0.0001, t=5.290) and 4.37±0.75 vs 20.62±3.59 seconds for genital investigation (P=0.0006, t=4.423). The duration of social nose contact in 3-NP-treated animals was lower than in the control rats; however, this difference was not statistically significant (24.37±3.49 vs 28.87±3.69 s, respectively, P=0.3909, t=0.885, Figure 1C). Total time spent on social behavior in the 3-NP group (41.12±3.80 s) decreased significantly compared to the control (76.37±6.73 s, P=0.0005, t=4.553, Figure 1D).
Non-social behaviors
There was a significant decrease in the rearing (P=0.0001, t=5.057, Figure 2A) and solitary behavior (P=0.0006, t=4.271, Figure 2D) time in the exposed rats compared with the control ones (28.00±3.52 vs 65.12±6.96 s for rearing and 282.0±13.14 vs 368.50±15.59 s for solitary behavior). Although self-grooming (P=0.154, t=1.495, Figure 2B) and exploring time (P=0.143, t=1.540, Figure 2C) showed decreasing trends, they did not differ significantly between the groups (46.30±6.09 vs 60.12±6.98 s for self-grooming and 207.70±12.50 vs 243.25±20.63 s for exploring). Additionally, considerably longer periods of immobility were seen in the injected group when compared to the control (177.77±25.62 vs 12.75±7.80 s, respectively, P<0.0001, t=5.842, Figure 2E).
Molecular analysis
Decreased GR levels 
In the ST, the GR level was significantly lower than in the control animals (P<0.0001, t=8.922, Figure 3A). The hippocampal GR level in the injected rats was also considerably lower than the control (P<0.0001, t=12.82, Figure 3B). However, the GR level in the PFC did not alter following the treatment (P=1.102, t=1.558, Figure 3C).

Declined FKBP5 levels 
The striatal FKBP5 level in 3-NP exposed rats was significantly lower than the control ones (P=0.024, t=2.651, Figure 3D). A considerable decrease was also observed in the level of the hippocampal FKBP5 compared to the control (P<0.0001, t=28.52, Figure 3E). Moreover, a noticeable decrease was detected in the FKBP5 level of PFC compared to the non-treated rats (P=0.0009, t=4.652, Figure 3F).

Decreased cytochrome content 
The quantity of striatal cytochrome aa3 (Cyt aa3), b (Cyt b), c (Cyt c), and c1 (Cyt c1) decreased significantly compared to the control group with the P <0.0001, and t were 8.526, 10.58, 7.37, and 7.642 respectively (Figure 4A). In the HIP, the 3-NP group had decreased content of Cyt aa3 (P<0.0001, t=6.967), Cyt b (P=0.0006, t=4.614), Cyt c (P=0.004, t=3.503), and Cyt c1 (P=0.003, t=3.597) compared with the non-treated animals (Figure 4B) meaningfully. According to the cytochrome contents of PFC, the 3-NP treatment decreased the levels of Cyt aa3 (P=0.019, t=2.793) and Cyt b (P=0.024, t=2.656). However, the levels of Cyt c and Cyt c1 did not alter following the 3-NP treatment (P=0.648, t=0.470, and P=0.361, t=0.955, respectively, Figure 4C) compared to the control group.
Decreased MAO-A and MAO-B activities 
Compared with the control group, the MAO-A activity was significantly lower in the 3-NP-treated animals in STR (50.40% of control, P=0.001, t=3.994), HIP (80.75% of control, P=0.006, t=3.262), and PFC (81.45% of control, P=0.023, t=2.556). Similarly, MAO-B activity in the 3-NP group showed a significant decline in STR (P=0.001, t=3.939), HIP (P=0.007, t=3.158), and PFC (P=0.043, t=2.242) compared to the control groups (39.84, 78.20, and 81.76% of control, respectively; Figures 5A- 5F). 
4. Discussion
We found that 3-NP treatment impaired the social behavior index. Certain non-social behaviors have also been impacted. It also reduced GR, FKBP5 protein levels, cytochrome contents, and MAO-A and MAO-B activities in the studied brain regions.
Many medical conditions with mitochondrial failure can impair social behavior, including cerebral hypoperfusion (Lee et al., 2015), hypoxia (Chauhan et al., 2022), ischemia (Girard et al., 2014), Alzheimer’s disease (Filali et al., 2011), or autism spectrum disorders (Frye, 2020; Rossignol & Frye, 2012). Numerous animal studies have investigated affective symptoms in these disorders (Prasad & Hung, 2020; Ruan & Yao, 2020; Southwell et al., 2018). The literature suggests that the inhibition of complex I in adulthood leads to reduced social interaction (Madiha & Haider, 2019; Siena et al., 2021). However, the role of mitochondrial complex II in regulating social behaviors remains unknown. It subsequently inspired the concept of designing this study.
There is also cumulative evidence showing our studied brain regions’ participation in processing social behaviors. For example, social interaction in rats has been reported to be associated with increased c-Fos expression as a marker of cellular activity in PFC and ST (van Kerkhof et al., 2014). The inactivation of different subregions of PFC impairs play behavior (van Kerkhof et al., 2013). Also, impaired glutamatergic signaling in the ST and HIP modulates social behavior (Finlay et al., 2015; van Kerkhof et al., 2013). The structural features like dendritic length and density of dendritic spines in PFC and HIP (Silva-Gomez et al., 2003) and the oxidative state in PFC and ST (Moller et al., 2011) affect this behavior. 
We found that 3-NP significantly impairs social interaction. It reduced the duration of play behavior, genital investigation, and the total time spent on social behaviors. These findings are in line with the aforementioned conditions of mitochondrial failure. 3-NP is also used to replicate HD symptoms in rats. Similar to our observations, HD transgenic animals also show reduced levels of social interaction (Manfré et al., 2018; Wood & Morton, 2015). However, a study also reports no social interaction deficit following 3-NP exposure (Wiprich et al., 2020). This controversy might be attributed to the different animal models (zebrafish) and experimental conditions used in the study. 
In addition, the duration of non-social behaviors of the animals revealed a decrease in the time spent on rearing and solitary behavior. It also showed an increase in the duration of immobility. These findings, demonstrating impaired motion activity following 3-NP injection, are consistent with previous studies (Duan et al., 2000; Thangarajan et al., 2014).
Investigations show restraint stress (Chiba et al., 2012), social defeat stress (Buwalda et al., 2001), prenatal stress (Weinstock, 2008), early-life maternal separation (Aisa et al., 2008), and low maternal care (Weaver et al., 2004; Weaver et al., 2006) can decrease GR levels in different brain regions. This reduction is associated with psychiatric symptoms like anxiety and depression. Beyond these physical and emotional stresses, metabolic stress may also reduce the GR level in the brain and cause behavioral abnormalities.
Here, we found that 3-NP reduces the GR level in the ST and HIP regions. These findings align with those of other studies in which the normal energetic function of mitochondria in the brain is impaired. For example, maternal hypoxia in rats causes a decrease in the GR level in the HIP of both male and female fetuses (Gonzalez-Rodriguez et al., 2014). Also, a study on adult rats demonstrates that transient ischemia in the brain reduces GR levels in the HIP (Pang et al., 2015). It is reported that transient brain ischemia can also reduce the GR level in the cortex of newborn rats (Lee et al., 2007). We also found a declining trend in the amount of this receptor in the PFC; however, this was not statistically significant. It may be because the frontal cortex consists of different subregions. Each of these subregions may have different biochemical capacities and reactions.
One reason for the decreased GR level may be the epigenetic and post-translational changes. It is shown that even milder stressors inhibit GR gene expression by inducing epigenetic changes in the GR gene promoter and raising the level of a specific microRNA that lowers the GR mRNA expression (Mifsud et al., 2017). This process may become even more prominent when rats are subjected to a greater stress level, such as progressive mitochondrial failure. Also, the duration of treatment and chronic glucocorticoid increases can result in a compensatory downregulation of GR levels as well as a decrease in glucocorticoid binding (Burnstein et al., 1991; Dufour & McBride, 2019).
FKBP5 is another protein that is closely linked to GR signaling. Its level can mirror the efficiency of the GR signaling pathway (Menke et al., 2012; Vermeer et al., 2003). Stressors can cause alterations in the brain by influencing the interactions between GR and FKBP5 (Rowson et al., 2024). Studies on animal models have revealed that all brain regions can be affected by glucocorticoid induction of FKBP5 expression (Lee et al., 2010; Merkulov et al., 2017; Scharf et al., 2011). 
We found that 3-NP decreases FKBP5 levels in all the studied brain regions. Similar to our findings, two transgenic models of HD show significantly lower FKBP5 levels in the ST (Bailus et al., 2021) and generally higher corticosterone levels (Dufour & McBride, 2016). These findings show that FKBP5 level drops in the brain in this context of mitochondrial failure, even though glucocorticoid level increases.
Here, the decreased FKBP5 level can be justified through the hypothesized concept that in chronic stress, increased FKBP5 level by glucocorticoids reduces glucocorticoid effects on GR target gene expressions (like GR induction of FKBP5 biosynthesis) via restricting GR translocation to the nucleus. It has been suggested that, under chronic stress and stress-related psychological states, inappropriate downregulation of these genes contributes to glucocorticoid resistance (Merkulov et al., 2017). 
Reduced GR signaling in the brain is a primary pathophysiology of psychiatric disorders (Hasler, 2010; Tsigos & Chrousos, 2002). For example, post-mortem studies have shown lower GR expression levels in different brain regions of individuals with major depressive disorder (MDD) than in controls (Alt et al., 2010). Patients with MDD also have lower GR sensitivity in their peripheral tissues, which can be a proper reflection of GR sensitivity in the brain (Pariante, 2004). 
In rodents, many environmental factors mentioned earlier induce anxiety and depression by reducing GR signaling in the brain (Aisa et al., 2008; Weaver et al., 2004; Weaver et al., 2006; Weinstock, 2008). Downregulation of GR in the forebrain can impair the HPA axis balance and increase levels of corticosterone and depression-like behaviors (Boyle et al., 2005). 3-NP exposure also induces anxiety and depression (Khodagholi et al., 2022). The current study suggests that reduced levels of GR in the ST and HIP can be grounds for 3-NP-related social behavior impairment. Even in the PFC, where we only found a falling trend without a significant change in GR level, decreased FKBP5 level may indicate an attenuated GR signaling pathway.
Beyond anxiety and depression, social behaviors are also closely modulated by HPA axis activity. For example, restraint stress that increases HPA activity and corticosterone levels (Flores et al., 1990) can impair social interaction behaviors (Zain et al., 2019). Social defeat stress also acts similarly (Iniguez et al., 2014). Although social behaviors have been studied in other contexts with mitochondrial failure, the underlying relation behind that is less known. Based on our findings, it can be hypothesized that 3-NP reduces GR levels in the brain, which may lead to HPA axis overactivity and result in impaired social behaviors. 
For a more accurate assessment of the effects of complex II inhibition by 3-NP treatment, measuring key variables in the next steps of the mitochondrial respiratory chain, including kinds of cytochromes, can offer a broader view of the affected processes. We observed that 3-NP reduces various cytochrome levels in different studied brain regions. Previously, the ST has shown reduced cytochrome contents following 3-NP exposure, per our findings (Mehrotra et al., 2015; Sandhir et al., 2014). In the current study, Cyt aa3 and Cyt b were significantly reduced in all studied regions compared to the control group. Cyt c and Cyt c1 also revealed significant decreases in the ST and hippocampal areas. However, their levels did not alter in the PFC. The simultaneous reduction of Cyt b related to complex III and Cyt aa3 of complex IⅤ, while no change in Cyt c and Cyt c1, probably indicates the greater resistance of these cytochromes to 3-NP treatment in the PFC. It may also be related to the compensatory responses in PFC.
MAO is a fundamental brain enzyme located mainly on the outer membrane of the mitochondria (Youdim et al., 2006). MAO-A and MAO-B are two types of this enzyme that metabolize monoamines (e.g. dopamine, serotonin, noradrenaline) in the brain and other tissues (Markey, 2007). According to investigations, alteration in MAO enzymatic activity may have significant impacts on controlling behavior and contribute to the pathogenesis of a wide range of mental disorders and neurodegenerative diseases, from antisocial personality disorder to Parkinson disease (Bortolato & Shih, 2011). MAO inhibitors are therapeutic agents for improving symptoms of affective disorders like depression (Pletscher, 1991; Yanez et al., 2012). Inhibition of this enzyme is also beneficial in the treatment of anxiety disorders like social anxiety disorder (Williams et al., 2017). However, MAO might have a different role when the neurons are under the pressure of mitochondrial failure.
In the current study, MAO-A and MAO-B activities decreased significantly in 3-NP-treated animals in ST and HIP compared to the control group. It was different from our initial expectations since post-mortem studies of HD patients show that MAO-A and MAO-B levels increase in several brain regions (Richards et al., 2011). However, we found that our findings are in line with previous studies in which 3-NP administration has been shown to reduce total MAO activity in the ST (Chakraborty et al., 2014; Haider et al., 2022; Salman et al., 2022; Salman et al., 2022). Also, according to another study, 3-NP most likely reduces dopamine breakdown in isolated striatal nerve terminals by indirectly lowering MAO-A activity (Herrera-Mundo & Sitges, 2010).
In the lack of a clear-cut explanation for the controversies mentioned, it seems that unequal MAO-A and MAO-B responsibilities for metabolizing different monoamines in various species (Youdim et al., 2006), the different potential affinity of these enzymes and the monoamine dynamics under mitochondrial failure in the brain (Chakraborty et al., 2014; Eradiri & Starr, 1999; Jamwal & Kumar, 2016; Johnson et al., 2000; Kraft et al., 2009; Kumar et al., 2010) can be the causes of these observations.
Furthermore, 3-NP can also reduce the dopamine and norepinephrine levels in brain regions like ST, cortex, and HIP, even when the MAO activity is decreased (Kumar et al., 2010; Salman et al., 2022). It shows that MAO activity might not be the pivotal modulator of the monoamine dynamic in the brain. However, lower activity of these enzymes may lead to behavioral changes. For example, lower activity of the MAO-A enzyme in the human brain is related to more aggressive behaviors, which is the opposite of social behavior (Alia-Klein et al., 2008).
Also, recent studies show that MAO activity not only fails to increase the cytosolic hydrogen peroxide (H2O2) but also activates the electron transport chain and ATP production by shuttling electrons to the intermembrane space of mitochondria (Graves et al., 2020). Together with our findings, it can be suggested that 3-NP-induced reduction in MAO-A and MAO-B activities prevents the cells from a potentially compensating role of MAO activity and can exacerbate mitochondrial failure. However, determining the key players in the molecular and behavioral consequences of 3-NP still needs more investigation. Study of stress or other neurotoxic effects of 3-NP, except mitochondrial dysfunction, along with behavioral changes in future research might disclose this toxin’s more exact mechanism of action.
Ethical Considerations
Compliance with ethical guidelines
All animal care and experimental procedures were performed in accordance with the guidelines of the National Health Association and had the approval of the Shahid Beheshti University of Medical Sciences Ethics Committee and Neuroscience Research Center Ethics Board, Tehran, Iran (Code: IR.SBMU.PHNS.REC.1399.167).
Funding
This Study was supported by the Neuroscience Research Center of Shahid Beheshti University of Medical Sciences, Tehran, Iran (Grant No.: 27336-1).
Authors' contributions
 Conceptualization and study design: Fatemeh Nasehi, Fariba Khodagholi, and Forough Foolad; Experiments: Fatemeh Nasehi, and Neda Kaveh; Data analysis: Fatemeh Nasehi, Neda Kaveh, Arman Zeinaddini-Meymand, and Maryam Alsadat Mousavi; Data interpretation and writing the original draft: Fatemeh Nasehi, Ali Maleki, Arman Zeinaddini-Meymand, Maryam Alsadat Mousavi, and Dariush Minai-Tehrani. Review and editing: Fariba Khodagholi. Forough Foolad, Ali Maleki, and Dariush Minai-Tehrani; Supervision: Fariba Khodagholi, and Forough Foolad; Final approval: All authors.
Conflict of interest
The authors declared no competing interests.
Acknowledgments
The authors appreciate the support of Neuroscience Research Center of Shahid Beheshti University of Medical Sciences, Tehran, Iran.


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