Structural and functional integration of human forebrain organoids with the injured adult rat visual system.

Brain organoids created from human pluripotent stem cells represent a promising approach for brain repair. They acquire many structural features of the brain and raise the possibility of patient-matched repair. Whether these entities can integrate with host brain networks in the context of the injured adult mammalian brain is not well established. Here, we provide structural and functional evidence that human brain organoids successfully integrate with the adult rat visual system after transplantation into large injury cavities in the visual cortex. Virus-based trans-synaptic tracing reveals a polysynaptic pathway between organoid neurons and the host retina and reciprocal connectivity between the graft and other regions of the visual system. Visual stimulation of host animals elicits responses in organoid neurons, including orientation selectivity. These results demonstrate the ability of human brain organoids to adopt sophisticated function after insertion into large injury cavities, suggesting a translational strategy to restore function after cortical damage.

Multichannel Silicon Probes for Awake Hippocampal Recordings in Large Animals.

Decoding laminar information across deep brain structures and cortical regions is necessary in order to understand the neuronal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. A lack of long-length probes with appropriate stiffness allowing penetration to deeper structures with minimal damage to the neural interface is one of the major technical limitations to applying the approaches currently utilized in lower order animals to large animals. We therefore tested the performance of multichannel silicon probes of various solutions and designs that were developed specifically for large animal electrophysiology. Neurophysiological signals from dorsal hippocampus were recorded in chronically implanted awake behaving Yucatan pigs. Single units and local field potentials were analyzed to evaluate performance of given silicon probes over time. EDGE-style probes had the highest yields during intra-hippocampal recordings in pigs, making them the most suitable for chronic implantations and awake behavioral experimentation. In addition, the cross-sectional area of silicon probes was found to be a crucial determinant of silicon probe performance over time, potentially due to reduction of damage to the neural interface. Novel 64-channel EDGE-style probes tested acutely produced an optimal single unit separation and a denser sampling of the laminar structure, identifying these research silicon probes as potential candidates for chronic implantations. This study provides an analysis of multichannel silicon probes designed for large animal electrophysiology of deep laminar brain structures, and suggests that current designs are reaching the physical thresholds necessary for long-term (∼1 month) recordings with single-unit resolution.

Electrophysiological Signature Reveals Laminar Structure of the Porcine Hippocampus.

The hippocampus is integral to working and episodic memory and is a central region of interest in diseases affecting these processes. Pig models are widely used in translational research and may provide an excellent bridge between rodents and nonhuman primates for CNS disease models because of their gyrencephalic neuroanatomy and significant white matter composition. However, the laminar structure of the pig hippocampus has not been well characterized. Therefore, we histologically characterized the dorsal hippocampus of Yucatan miniature pigs and quantified the cytoarchitecture of the hippocampal layers. We then utilized stereotaxis combined with single-unit electrophysiological mapping to precisely place multichannel laminar silicon probes into the dorsal hippocampus without the need for image guidance. We used in vivo electrophysiological recordings of simultaneous laminar field potentials and single-unit activity in multiple layers of the dorsal hippocampus to physiologically identify and quantify these layers under anesthesia. Consistent with previous reports, we found the porcine hippocampus to have the expected archicortical laminar structure, with some anatomical and histological features comparable to the rodent and others to the primate hippocampus. Importantly, we found these distinct features to be reflected in the laminar electrophysiology. This characterization, as well as our electrophysiology-based methodology targeting the porcine hippocampal lamina combined with high-channel-count silicon probes, will allow for analysis of spike-field interactions during normal and disease states in both anesthetized and future awake behaving neurophysiology in this large animal.

Diazepam reverses increased anxiety-like behavior, social behavior deficit, and dopamine dysregulation following withdrawal from acute amphetamine.

Psychostimulants such as amphetamine (AMPH) increase dopamine (DA) release from ventral tegmental area (VTA) neurons, which is associated with their acute reinforcing actions. This positive state is followed by a negative affective state during the withdrawal period each time the drug is taken (i.e., opponent process theory). AMPH withdrawal is accompanied by symptoms of anxiety and depression, which are associated with DA system dysfunction in humans and animal models. Most studies have focused on the negative affective state after withdrawal from chronic drug administration; yet, this negative state appears even after a drug is taken for the first time in both humans and rodents. In rats, withdrawal from a single dose of AMPH (2 mg/kg) increases forced swim test immobility and decreases the number of spontaneously active VTA DA neurons up to 48 h post-withdrawal. In the current study, acute AMPH withdrawal was found to increase anxiety-like behavior in the elevated plus maze (EPM), reduce social cage time in the three-chambered social approach test (SAT), and attenuate VTA population activity. The effects of diazepam, a drug commonly used to treat anxiety disorders, were tested on anxiety-like and social behavior as well as VTA DA neuron activity following acute AMPH withdrawal. A single (5 mg/kg) dose of diazepam circumvented the neurobehavioral effects induced by acute AMPH withdrawal, as demonstrated by increased open arm time and social cage time as well as normalized VTA DA activity comparable to controls, suggesting that these neurobehavioral effects of acute AMPH withdrawal reflect an anxiety-like state.

Divergent effects of acute and repeated quetiapine treatment on dopamine neuron activity in normal vs. chronic mild stress induced hypodopaminergic states.

Clinical evidence supports the use of second-generation dopamine D2 receptor antagonists (D2RAs) as adjunctive therapy or in some cases monotherapy in patients with depression. However, the mechanism for the clinical antidepressant effect of D2RAs remains unclear. Specifically, given accumulating evidence for decreased ventral tegmental area (VTA) dopamine system function in depression, an antidepressant effect of a medication that is expected to further reduce dopamine system activity seems paradoxical. In the present paper we used electrophysiological single unit recordings of identified VTA dopamine neurons to characterize the impact of acute and repeated administration of the D2RA quetiapine at antidepressant doses in non-stressed rats and those exposed to the chronic mild stress (CMS) rodent depression model, the latter modeling the hypodopaminergic state observed in patients with depression. We found that acute quetiapine increased dopamine neuron population activity in non-stressed rats, but not in CMS-exposed rats. Conversely, repeated quetiapine increased VTA dopamine neuron population activity to normal levels in CMS-exposed rats, but had no persisting effects in non-stressed rats. These data suggest that D2RAs may exert their antidepressant actions via differential effects on the dopamine system in a normal vs. hypoactive state. This explanation is supported by prior studies showing that D2RAs differentially impact the dopamine system in animal models of schizophrenia and normal rats; the present results extend this phenomenon to an animal model of depression. These data highlight the importance of studying medications in the context of animal models of psychiatric disorders as well as normal conditions.