Reduced expression of Nogo-A leads to motivational deficits in rats

I know this is in rats but who is going to take the lead in researching this in humans? Survivors need tons of motivation since our doctors are leaving us disabled with no path to get to full recovery. It however helps to inhibit nogo-A for recovery.

Inhibition of Nogo: a key strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system

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Reduced expression of Nogo-A leads to motivational deficits in rats

Thomas Enkel¹*, Stefan M. Berger¹, Kai Schönig¹, Björn Tews² and Dusan Bartsch¹

• ¹Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
• ²Schaller Research Group, Division of Molecular Mechanisms of Tumor Invasion, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany

Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Mice lacking Nogo-A, or rats with neuronal Nogo-A deficiency, exhibit behavioral abnormalities such as impaired short-term memory, decreased pre-pulse inhibition, and behavioral inflexibility. In the current study, we extended the behavioral profile of the Nogo-A deficient rat line with respect to reward sensitivity and motivation, and determined the concentrations of the monoamines dopamine and serotonin in the prefrontal cortex (PFC), dorsal striatum (dSTR), and nucleus accumbens (NAcc). Using a limited access consumption task, we found similar intake of a sweet condensed milk solution following ad libitum or restricted feeding in wild-type and Nogo-A deficient rats, indicating normal reward sensitivity and translation of hunger into feeding behavior. When tested for motivation in a spontaneous progressive ratio task, Nogo-A deficient rats exhibited lower break points and tended to have lower “highest completed ratios.” Further, under extinction conditions responding ceased substantially earlier in these rats. Finally, in the PFC we found increased tissue levels of serotonin, while dopamine was unaltered. Dopamine and serotonin levels were also unaltered in the dSTR and the NAcc. In summary, these results suggest a role for Nogo-A regulated processes in motivated behavior and related neurochemistry. The behavioral pattern observed resembles aspects of the negative symptomatology of schizophrenia.

Introduction

Nogo-A is an important neurite growth-regulatory protein in the developing and adult nervous system (Schwab, 2010). While research originally focused on oligodendrocytic Nogo-A and its role in injury and repair of fiber tracts in the CNS, the fact that Nogo-A was found to be present also in neurons (Huber et al., 2002) has risen interest in its involvement in the generation of general behavior, as well. Indeed, in a wide-ranging analysis, Willi et al. (2009, 2010) could demonstrate behavioral alterations in Nogo-A knockout (Nogo-A^−/−) mice.

Recently, Nogo-A deficiency could be established in the rat species by using a transgenic, constitutively expressed artificial microRNA leading to a 50% reduction of Nogo-A levels in neurons (Tews et al., 2013). Similar to Nogo-A^−/− mice, these Nogo-A deficient rats exhibited a variety of behavioral deficits, such as reduced pre-pulse inhibition of the acoustic startle response, behavioral inflexibility, and impairments in short-term memory. In addition, pronounced alterations in social behavior were found. Conducting basic research or preclinical studies in rats offer the advantage that, for example, they more readily learn difficult cognitive behavioral tasks and exhibit more complex social behaviors than mice (Poole and Fish, 1975; McNamara et al., 1996; Costantini and D’Amato, 2006; Cressant et al., 2007). Further, the rat Nogo-A knockdown model uses the well-characterized Sprague Dawley outbred strain and therefore offers increased translational value compared to inbred mice, which is particularly important when evaluating a possible role of neuronal growth regulation in psychiatric disorders (Tews et al., 2013). This latter point is of interest, as the behavioral and structural phenotypes of Nogo-A^−/− mice and Nogo-A deficient rats make them potential tools to investigate the pathology of schizophrenia (SCZ; Kristofikova et al., 2013; Willi and Schwab, 2013).

Schizophrenia is a common and debilitating psychiatric disorder and believed to result from neurodevelopmental disturbances (Keshavan et al., 2008; Tandon et al., 2008; Lewis and Sweet, 2009). Interestingly, neuronal Nogo-A is highly expressed particularly during early neuronal development and down regulated later during adulthood in most regions, except the hippocampus, suggesting an important role in neuronal network formation (Huber et al., 2002; Kempf and Schwab, 2013; Mironova and Giger, 2013). In the current study, we aimed to investigate the consequences of Nogo-A deficiency with respect to two important aspects of the negative spectrum of SCZ symptoms, which have not yet been explored in rats nor in mice: avolition, a decrease in the motivation to take action and pursue goals, and anhedonia, the reduced ability to experience positive affect through reward (Tandon et al., 2009). The negative symptoms of SCZ have been particularly linked to genetic liability and neurodevelopmental disturbances (Dominguez et al., 2010). Further, it has been described before that interference with neuronal development by lesioning the neonatal brain can affect reward sensitivity (Le Pen et al., 2002) or motivated behavior (Schneider and Koch, 2005).

Motivational states in rats can be made accessible to quantification by the use of operant progressive ratio schedules introduced by Hodos and colleagues (Hodos, 1961; Hodos and Kalman, 1963). In this test, subjects need to exhibit progressively increasing effort (more lever pressing) to gain a stable amount of reward; the operant demand at which reward-related responding ceases is termed the “break point” and can serve as an index for reinforcer efficacy or a rat’s motivational state (Barr and Phillips, 1998; Reilly, 1999; Mobini et al., 2000). In the Nogo-A deficient rat, we employed the spontaneous progressive ratio test (PR-Test) and additionally assessed operant responding under extinction conditions, i.e., when rewards were completely omitted. Reward sensitivity was investigated in a well-validated limited access consumption task for sweet rewards (Enkel et al., 2010; Schneider et al., 2010). Finally, to relate behavioral findings to underlying neurochemistry, we analyzed dopamine and serotonin (5-HT) content in brain regions associated with reward processing, namely nucleus accumbens (NAcc), dorsal striatum (dSTR), and prefrontal cortex (PFC).