Early-life experiences altered the maturation of the lateral habenula in mouse models, resulting in behavioural disorders in adulthood

Abstract

Background: Abnormally high activity in the lateral habenula causes anxiety- or depression-like behaviours in animal experimental models. It has also been reported in humans that excessive stress in early life is correlated with the onset of psychiatric disorders in adults. These findings raise the question of whether maturation of the lateral habenula is affected under the influence of early-life experiences, which could govern behaviours throughout life. Methods: We examined the maturation of the lateral habenula in mice based on neuronal activity markers and plastic components: Zif268/Egr1, parvalbumin and perineuronal nets. We examined the effect of early-life stress using repeated maternal deprivation. Results: First, we found a transient highly sensitive period of the lateral habenula under stress. The lateral habenula matured through 4 stages: postnatal days 1–9 (P1–9), P10–20, around P35 and after P35. At P10–20, the lateral habenula was highly sensitive to stress. We also observed experience-dependent maturation of the lateral habenula. Only mice exposed to chronic stress from P10–20 exhibited changes specific to the lateral habenula at P60: abnormally high stress reactivity shown by Zif268/Egr1 and fewer parvalbumin neurons. These mice showed anxiety- or depression-like behaviours in the light–dark box test and forced swim test. Limitations: The effect of parvalbumin neurons in the lateral habenula on behavioural alterations remains unknown. It will be important to understand the “sensitive period” of the neuronal circuits in the lateral habenula and how the period P10–20 is different from P9 or earlier, or P35 or later. Conclusion: In mice, early-life stress in the period P10–20 led to late effects in adulthood: hyperactivity in the lateral habenula and anxiety or depression, indicating differences in neuronal plasticity between stages of lateral habenula maturation.

Inhibition Within the Lateral Habenula—Implications for Affective Disorders

“…These neurons have been shown to inhibit other LHb neurons to promote aggressive behaviour in mice (Flanigan et al, 2020) which, as mentioned earlier, can be interpreted as a reward-seeking behaviour (Golden et al, 2016). We and others have recently shown that some LHb neurons which express the well-known cortical interneuron marker parvalbumin (Tremblay et al, 2016) are GABAergic and inhibit local LHb neurons (Webster et al, 2020;Nakamura et al, 2021). These neurons are likely distinct from the aforementioned population of GAD-2 expressing neurons in that they are confined to the lateral LHb and also express the vesicular GABA transporter (VGAT; Webster et al, 2020), another well-known marker of inhibitory neurons, but largely do not express GAD-2 (Nakamura et al, 2021).…”

“…We and others have recently shown that some LHb neurons which express the well-known cortical interneuron marker parvalbumin (Tremblay et al, 2016) are GABAergic and inhibit local LHb neurons (Webster et al, 2020;Nakamura et al, 2021). These neurons are likely distinct from the aforementioned population of GAD-2 expressing neurons in that they are confined to the lateral LHb and also express the vesicular GABA transporter (VGAT; Webster et al, 2020), another well-known marker of inhibitory neurons, but largely do not express GAD-2 (Nakamura et al, 2021). Note however that the expression patterns of GABAergic markers within the LHb appears to differ between mice and rats (Quina et al, 2020), with VGAT expression in rats observed in the medial LHb and GAD-2 expression largely absent (Zhang et al, 2018;Quina et al, 2020).…”

“…It is well-accepted that the majority of LHb neurons form a physiologically homogenous, but morphologically diverse population (Weiss and Veh, 2011), of which most neurons are glutamatergic (Omelchenko et al, 2009;Brinschwitz et al, 2010). Yet mounting evidence now indicates the existence of locally-targeting inhibitory neurons (Zhang et al, 2018;Flanigan et al, 2020;Webster et al, 2020;Nakamura et al, 2021), which may form multiple distinct sub-classes. One such population express the inhibitory marker glutamic acid decarboxylase 2 (GAD-2) and are confined to the medial LHb (Flanigan et al, 2020).…”

Rodent models of early adversity: Impacts on developing social behavior circuitry and clinical implications

“…On the circuit level, previous SAM-LB adversity prevented maternal buffering of the mesolimbic dopamine (DA) circuit, including the ventral tegmentum (VTA), nucleus accumbens, and BLA, as well as the interface between the medial prefrontal cortex and the BLA (Barr et al, 2009 ). Recently, research by our group has expanded this circuit to show that adversity also prevents the mother's ability to regulate the lateral habenula (LHb), an important negative regulator of the midbrain DA circuitry (Baker and Mizumori, 2017 ; Fakhoury, 2017 ; Hu et al, 2020 , 2022 ; Germann et al, 2021 ; Nakamura et al, 2021 ; Packard et al, 2021 ).…”

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

“…PV expression shows up within the first two postnatal weeks following birth in rodents (Seto-Ohshima et al, 1990;de Lecea et al, 1995;Fishell, 2007;Marín, 2012;Bartolini, et al, 2013;Wong et al, 2018) and matures through the early juvenile period, marked by an increase in both intensity of PV expression and the number of PV-positive interneurons, as well as the formation and strengthening of PV interneuron synapses through perineuronal net (PNN) deposition, which is associated with the eventual closure of critical windows (Favuzzi et al, 2017;Bucher et al, 2021). Indeed, it has been hypothesized that PV-positive interneuron dysregulation during these developmental windows (Marín, 2012;Bartolini et al, 2013;Canetta et al, 2016;Santiago et al, 2018;Murthy et al, 2019;Gildawie et al, 2020;Ohta et al, 2020;Gildawie et al, 2021;Guadagno et al, 2021;Klimczak et al, 2021;Nakamura et al, 2021) be one of the key pathophysiological mechanisms contributing to the neurodevelopmental origins of multiple psychiatric disorders (Ferguson and Gao, 2018;Ruden et al, 2021), such as major depression (Fogaça and Duman, 2019;Spijker et al, 2020), bipolar disorder (Konradi et al, 2011), autism (Contractor et al, 2021) and schizophrenia (Lewis et al, 2012;Dienel and Lewis, 2019).…”