Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

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The molecular neurobiology of depression

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

The role of inflammation in depression: from evolutionary imperative to modern treatment target

Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions

The Mesolimbic Dopamine Reward Circuit in Depression

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented sleep bouts, atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2/CACNG2, variants in which have been identified in patients with bipolar disorder and schizophrenia.

On the Mental Status of Stargazer Mice

Disability in patients with epilepsy (PWE) is multifactorial: beyond seizure frequency/severity, PWE are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly impact quality of life. In this study, we explored how variations in epilepsy severity and the burden of self-reported somatic/neuropsychiatric symptoms are associated with disruptions to 24h activity patterns (rest-activity rhythms, RARs), determined through wrist accelerometry/actigraphy. Continuous multiday recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously provided responses to a range of validated psychometric instruments to measure the burden of anxiety, depression, sleepiness, and somatic symptoms. As a comparator, we conducted a similar psychometric-actigraphic correlation in 1761 subjects of Hispanic origin (35% male, ages 18-65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying RAR amplitude, steepness, acrophase and robustness) and non-parametric measures to estimate RAR stability, fragmentation, and sleep. Compared with age- and sex-matched SOL subjects, RARs from PWE subjects featured a significantly diminished amplitude, a wider rest phase and significantly more total daily sleep. Within PWE, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy. In contrast, high anxiety, depression, and somatic symptom scores were associated with diminished RAR robustness and a delayed acrophase. We applied the complete SOL Sueño database to train logistic regression models to dichotomously classify anxiety, depression and sleepiness symptoms using age, sex, body mass index and a range of non-collinear RAR parameters. When tested on PWE, these models predicted prevalent anxiety and depression symptoms with modest success (accuracy ∼70%) but failed to predict subjective sleepiness. Together, these results demonstrate that RAR features may vary with depression and anxiety symptoms in ambulatory patients with focal epilepsy, potentially offering a set of objective wearable-derived endpoints to adjunct routine clinical care and drug/device treatment trials. With larger actigraphic-psychometric datasets in PWE, we may identify RAR signatures that can more precisely distinguish between variations in seizure risk, the burden of anticonvulsant therapy and prevalent mood/anxiety symptoms.

Vaishnav Krishnan

Papers

On the Mental Status of Stargazer Mice

Actigraphic Correlates of Neuropsychiatric Disability in Adult Patients with Focal Epilepsy