Laser microscopy has generally poor temporal resolution, caused by the serial scanning of each pixel. This is a significant problem for imaging or optically manipulating neural circuits, since neuronal activity is fast. To help surmount this limitation, we have developed a “scanless” microscope that does not contain mechanically moving parts. This microscope uses a diffractive spatial light modulator (SLM) to shape an incoming two-photon laser beam into any arbitrary light pattern. This allows the simultaneous imaging or photostimulation of different regions of a sample with three-dimensional precision. To demonstrate the usefulness of this microscope, we perform two-photon uncaging of glutamate to activate dendritic spines and cortical neurons in brain slices. We also use it to carry out fast (60 Hz) two-photon calcium imaging of action potentials in neuronal populations. Thus, SLM microscopy appears to be a powerful tool for imaging and optically manipulating neurons and neuronal circuits. Moreover, the use of SLMs expands the flexibility of laser microscopy, as it can substitute traditional simple fixed lenses with any calculated lens function.

Identifying biomarkers for major depression is of high importance for improving diagnosis and treatment of this common and debilitating neuropsychiatric disorder, as the field seeks to move toward both personalized and more effective treatments. Here we focus on electroencephalography (EEG) or direct scalp voltage recordings as such a biomarker, with an emphasis on gamma and high gamma oscillations (or “rhythms”). In the last several decades, alpha and theta band rhythms have been found to provide information on depressive state as well as recovery, but the gamma band is less well characterized with respect to depression. We summarize some key findings on gamma rhythms (especially their amplitude) as a biomarker or endophenotype for major depression. These studies suggest: (1) under certain conditions gamma rhythms can distinguish subjects with major depression from healthy controls, (2) gamma may distinguish bipolar disorder from unipolar depression, (3) various pharmacological and non-pharmacological treatments that counteract depression also alter gamma, (4) animal models of depression-like behavior show gamma abnormalities, with changes in gamma associated with therapeutic recovery. The most informative approaches in the future may combine profiles of gamma band power across the brain to assess ratios of activity across regions. Overall we have good evidence to suggest that gamma rhythms may provide objective information on major depressive disease status, but we will need further work to better define the precise measures to follow.

Major depression is a stress-linked disease with significant morbidity and the anesthetic drug ketamine is of growing interest in the treatment of depression, since in responsive individuals a single dose has rapid (within hours) antidepressant effects that can be sustained for over a week in some instances. This combination of fast action and a therapeutic effect that lasts far beyond the drug’s half-life points to a unique mechanism of action. In this reverse translational study, we investigate the degree to which ketamine counteracts stress-related depression-like behavioral responses by determining whether it affects unstressed animals similarly to stressed mice. To test this, male C57BL/6J mice were given a single injection of vehicle (0.9% saline; i.p.), 10 mg/kg ketamine, or 30 mg/kg ketamine, and were tested in the forced swim test (FST) 24 hours and 7 days later, as well as in the open field test on the eighth day. Unstressed mice had normal group housing, environmental enrichment, and experimenter pre-handling (5 days), whereas stressed animals were subjected to chronic mild stress (single housing, reduced enrichment and minimal handling), where some mice also had daily two-week unpredictable chronic stress (UCS). We find that ketamine (24 hours post-injection) decreases immobility and increases mobile (swimming) behavior (antidepressant-like effects) in UCS animals but does the opposite in unstressed mice, similar to recent human findings. In summary, these data suggest that chronic psychological stress interacts with ketamine treatment to modulate its effects in the C57BL/6J mouse FST, which reinforces the relevance of this test, and this strain of mice, to human, stress-induced depression.

Brain states are traditionally recognized via sleep-wake cycles, but modern neuroscience is beginning to identify many sub-states within these larger arousal types. Multiple lines of converging evidence now point to the infraslow oscillation (ISO) as a mediator of brain sub-states, with impacts ranging from the creation of resting state networks (RSNs) in awake subjects to interruptions in neural activity during sleep. This review will explore first the basic characteristics of the ISO in human subjects before reviewing findings in sleep and in animals. Networks of consistently correlated brain regions known as RSNs seen in human functional neuroimaging studies oscillate together at infraslow frequencies. The infraslow rhythm subdivides nonREM in a manner that may correlate with plasticity. The mechanism of this oscillation may be found in the thalamus and may ultimately come from glial cells. Finally, I review the functional impacts of ISOs on brain phenomena ranging from higher frequency oscillations, to brain networks, to information representation and cognitive performance. ISOs represent a relatively understudied phenomenon with wide effects on the brain and behavior.

Discovering that the anesthetic drug ketamine has rapidly acting antidepressant effects in many individuals with major depression is one of the most important findings in clinical psychopharmacology in recent decades. The initial report of these effects in human subjects was based on a foundation of rodent preclinical studies carried out in the 1990s, and subsequent investigation has included both further studies in individuals with depression, as well as reverse translational experiments in animal models, especially rodents. While there is general agreement in the rodent literature that ketamine has rapidly-acting, and generally sustained, antidepressant-like properties, there are also points of contention across studies, including the precise mechanism of action of this drug. In this review, we briefly summarize prominent yet variable findings regarding the mechanism of action. We also discuss a combination of similarities and variances in the rodent literature in the antidepressant-like effects of ketamine as a function of dose, species and strain, test, stressor, and presumably sex of the experimenter. We then present previously unpublished mouse strain comparison data suggesting that subanesthetic ketamine does not have robust antidepressant-like properties in unstressed animals, and may actually promote depression-like behavior, in contrast to widely reported findings. We conclude that the data best support the notion of ketamine action principally via NMDA receptor antagonism, transiently boosting glutamatergic (and possibly other) signaling in diverse brain circuits. We also suggest that future studies should address in greater detail the extent to which antidepressant-like properties of this drug are stress-sensitive, in an effort to better model major depression present in humans.