t and depression-like behavior (Raison et al. 2009). Patients with major depression have increased blood proinflammatory markers and antidepressant therapy is associated with decreases in markers. In addition to increased innate immune gene expression, human depression involves structural changes in hippocampus with multiple studies finding hippocampal volume is decreased in patients with depression (Videbech and Ravnkilde 2004). Other studies have associated loss of hippocampal neurogenesis, the formation of new neurons, with depression and hippocampal shrinkage. Interestingly, antidepressants increase hippocampal neurogenesis in models of depression and increase humans hippocampal volume during reversal of depression (Dranovsky and Hen 2006). Stress, multiple addictive drugs, innate immune genes and other factors that precipitate depression, reduce hippocampal neurogenesis (Tanapat et al. 2001; Malberg and Duman 2003; Gregus et al. 2005). Factors that reduce neurogenesis increase depression-like behavior (Johnson et al. 2006). Activation of NF-κB is necessary for stress induced inhibition of neurogenesis and induction of depression-like behavior (Koo and Duman 2008) as well as social defeat models of depression (Christoffel et al. 2011). Further, antidepressant efficacy in rodent behavioral models requires hippocampal neurogenesis (Santarelli et al. 2003). In animal studies, endotoxin induced increases in innate immune genes reduce neurogenesis and increase depression-like behavior (Kelley 2011). TLRs are necessary components of both ethanol neurotoxicity (Alfonso-Loeches et al. 2010) and innate immune induced depressive behavior and reduction of neurogenesis (Kelley 2011). TLR, glutamate hyperexcitability and endogenous TLR agonists lead to persistent increases in brain hyperexcitability (Maroso et al. 2010). We have found that chronic ethanol increases brain innate immune genes, reduces brain neurogenesis and increases depression-like behavior (Stevenson et al. 2009) (Fig. 4.) Ethanol induced loss of neurogenesis paralleled the onset of depression-like behavior with both reversed by anti-depressant treatment (Stevenson et al. 2009). Similarly stress induced IL-1β reduces neurogenesis causing depression like behavior (Koo and Duman 2008). Thus, neurogenesis reflects mood, with reduced neurogenesis associated with innate immune gene induction, drug induced negative affect and depression-like behavior. Interestingly, recovery from alcoholism is associated with improved mood and cognition, human brain enlargement and increased neurogenesis (Crews and Nixon 2009). Overall findings suggest adult hippocampal stem cells and neurogenesis provide an index of mood and negative affect that allow molecular studies on regulation of mood, both negative and positive (Crews and Nixon 2003; Koo et al. 2011) (Fig.4). These findings are consistent with drug induced depression sharing common mechanisms with endogenous depression as well as the negative affect of substance use disorder, e. g. addiction.
The frontal cortex is involved in attention, rule setting, decisions and behavioral control. It connects to multiple brain regions through excitatory glutamatergic neurons. Reciprocal connections to thalamus and limbic regions involve focal excitation that is disrupted by innate immune gene induction. In astrocytes, activation of NF-κB increasing expression of proinflammatory innate immune genes (Zou and Crews 2006; Pascual et al. 2007; Zou and Crews 2010) and reduces astrocyte glutamate transport (Zou and Crews 2005) causing an increase in extracellular glutamate increasing neuron excitiation and excitotoxicity (Zou and Crews 2006). Innate immune induced hyperexcitability due to loss of cortical glutamate transporters inactivates the frontal lobes contributing to the neurobiology of addiction (Crews et al. 2006). Other studies have indicated genetic factors linked to a hyperglutamate state to alcoholism (Spinagel, 2005) and ethanol induced NF-κB activation to increased extracellular glutamate (Ward et al. 2009). Innate immune gene inducti