The discovery of newborn neurons in the adult brain has generated enormous interest over the past decade. Although this process is well documented in the hippocampus and olfactory bulb, the possibility of neuron formation in other brain regions is under vigorous debate. Neurogenesis within the adult hippocampus is suppressed by factors that predispose to major depression and stimulated by antidepressant interventions. This pattern has generated the hypothesis that impaired neurogenesis is pathoetiological in depression and stimulation of newborn neurons essential for effective antidepressant action. This review critically evaluates the evidence in support of and in conflict with this theory. The literature is divided into three areas: neuronal maturation, factors that influence neurogenesis rates, and function of newborn neurons. Unique elements in each of these areas allow for the refinement of the hypothesis. Newborn hippocampal neurons appear to be necessary for detecting subtle environmental changes and coupling emotions to external context. Thus speculatively, stress-induced suppression of neurogenesis would uncouple emotions from external context leading to a negative mood state. Persistence of negative mood beyond the duration of the initial stressor can be defined as major depression. Antidepressant-induced neurogenesis therefore would restore coupling of mood with environment, leading to the resolution of depression. This conceptual framework is provisional and merits evaluation in further experimentation. Critically, manipulation of newborn hippocampal neurons may offer a portal of entry for more effective antidepressant treatment strategies.

Many bacteria can form wall-deficient variants, or L-forms, that divide by a simple mechanism that does not require the FtsZ-based cell division machinery. Here, we use microfluidic systems to probe the growth, chromosome cycle and division mechanism of Bacillus subtilis L-forms. We find that forcing cells into a narrow linear configuration greatly improves the efficiency of cell growth and chromosome segregation. This reinforces the view that L-form division is driven by an excess accumulation of surface area over volume. Cell geometry also plays a dominant role in controlling the relative positions and movement of segregating chromosomes. Furthermore, the presence of the nucleoid appears to influence division both via a cell volume effect and by nucleoid occlusion, even in the absence of FtsZ. Our results emphasise the importance of geometric effects for a range of crucial cell functions, and are of relevance for efforts to develop artificial or minimal cell systems.

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14 15 16 2 SUMMARY 17Wall deficient variants of many bacteria, called L-forms, divide by a simple mechanism that 18 does not depend on the complex FtsZ-based cell division machine. We have used 19 microfluidic systems to probe the growth, chromosome cycle and division mechanism of 20 Bacillus subtilis L-forms. The results show that forcing cells into a narrow linear 21 configuration greatly improves the efficiency of cell growth and chromosome segregation. 22 This reinforces the view that L-form division is driven by an excess accumulation of surface 23 area over volume. Cell geometry was also found to play a dominant role in controlling the 24 relative positions and movement of segregating chromosomes. The presence of the 25 nucleoid appears to influence division both via a cell volume effect and by nucleoid 26 occlusion, even in the absence of the FtsZ machine. Overall, our results emphasise the 27 importance of geometric effects for a range of critical cell functions and are of relevance for 28 efforts to develop artificial or minimal cell systems. 29 30 31 32 33 34 35 36 37 38 39 40 41 42 44 45 76 al. Studer et al., 2016). Our current model for L-form proliferation assumes that 77 division is driven simply by an imbalance between volume and surface area. Support for this 78 idea comes from the fact that we have been unable to identify mutations in genes required 79 for division, other than those that upregulate membrane synthesis (Mercier et al., 2013). 80 Furthermore, there is a sound mathematical basis for the process (Svetina, 2009) and it has 81 even been replicated in vitro with simple lipid vesicle systems (Peterlin et al., 2009). The 82 simplicity of this division process has led to suggestions that L-form division may be a good 83 model for studying how primordial cells proliferated before the invention of "modern" 84 protein based division machines (Leaver et al., 2009; Chen, 2009; Briers et al., 2012; 85 Errington, 2013). It is also of interest as the basis for proliferation in simplified or artificial 86 cell systems (Blain and Szostak, 2014; Caspi and Dekker, 2014; Hutchison et al., 2016). 87 4 Detailed analysis of L-form proliferation has been hampered by the lack of effective systems 88 for following their growth and division by time-lapse imaging. The cells tend not to remain in 89 focus in liquid culture and attempts to tether them to surfaces can cause flattening and 90 lysis. Thus, many questions about their cell cycle remain unresolved, particularly the extent 91 to which chromosome replication and segregation can be controlled and coordinated with 92 growth and division in cells with pleomorphic shape and no cell wall. (Note that in this paper 93 because many of the cells observed are not undergoing division, we use the term 94 segregation for sister chromosomes that have visibly separated, whether or not a division 95 septum separates them.) 96 Here we report that the use of microfluidic devices that force L-forms into an elongated 97 shape, with cross section similar to...

Increasing neurogenesis enhances acquisition of novel experiences possibly by suppressing activation of mature hippocampal neurons that mediate established, conflicting memories. Therefore, antidepressants may improve mood by stimulating new hippocampal neurogenesis that facilitate detection of positive experiences while suppressing interference from recurring depressogenic thought patterns.

In vitro miniaturized organoids are innovative tools with varying applications in biomedical engineering, such as drug testing, disease modeling, organ development studies, and regenerative medicine. However, conventional organoid development has several hurdles in reproducing and reconstituting organ-level functions in vitro, hampering advanced and impactful studies. In this review, we summarize the emerging microengineering-based organoid development techniques aiming to overcome these hurdles. First, we provide basic information on microengineering techniques, including those for reconstituting organoids with organ-level functions. We then focus on recent advances in microengineered organoids with better morphological, physiological, and functional characteristics than conventionally developed organoids. We believe that microengineered organoids possessing organ-level functions in vitro will enable widespread studies in the field of biological sciences and have clinical applications.