**Background:** Noradrenaline (NE) is a major brainstem neuromodulator implicated in arousal, mood, stress, attention, and memory. However, its precise role in regulating specific behavioral states remains unclear due to the limitations of prior approaches (e.g., pharmacological lesions, enzyme knockout models that also affect peripheral NE, or techniques targeting only the locus coeruleus). To overcome these limitations, the authors engineered a VMAT2^DBHcre^ mouse model in which the vesicular monoamine transporter-2 (VMAT2) gene is selectively spliced out in NE neurons via Cre-recombinase under the DBH promoter, resulting in brain-specific NE depletion while fully preserving peripheral NE and adrenaline transmission.
**Methods:** VMAT2^DBHcre^ KO and WT littermates (2–4 months old, C57Bl/6J background) underwent comprehensive behavioral testing including: elevated plus maze (EPM), novelty-suppressed feeding test (NSF), marble burying, forced swim test (FST) with citalopram and reboxetine, sucrose preference, contextual and cued fear conditioning, Morris water maze (spatial, reversal, and rapid-place learning versions), attentional set-shifting task (ASST), acute and sensitized locomotor responses to cocaine (5, 10, 20 mg/kg) and amphetamine (1, 3, 5 mg/kg), tail immersion nociception, circadian analysis via running wheels and telemetry, and 24-hour polysomnographic EEG/EMG recordings. Plasma corticosterone was measured at baseline, after 30-min restraint stress, and 90 min post-stress; dexamethasone suppression test assessed HPA axis negative feedback. Transcriptomic profiling was performed using Agilent Mouse 60k microarrays on micropunches from six brain regions (LC, VTA, raphe, NAc, PFC, DG) from 3-month-old male mice (n=4 pools per genotype). SV2c expression was validated by radioactive in situ hybridization and further examined in the LC of control, susceptible, and resilient mice following 10-day chronic social defeat stress (CSDS).
**Key Results:** In anxiety tests, KO mice showed significantly decreased latency to eat in the NSF (t_50=3.70, p=0.0005) and fewer marbles buried (t_33=2.07, p=0.047), with a non-significant trend in the EPM. In the FST, KO mice had decreased immobility versus WT (post-hoc p=0.0009), and reboxetine failed to reduce immobility in KO (p=0.30, ns), consistent with absent NE release. Sucrose preference was unchanged. Corticosterone levels were similar at baseline and after 30-min restraint, but KO mice showed faster return to baseline 90 min post-stress (post-hoc p=0.00017) and increased dexamethasone-induced suppression (t_8=2.72, p=0.026). In fear conditioning, KO mice exhibited increased contextual freezing (t_13=2.86, p=0.013) with no change in cued fear. Spatial and working memory in the Morris water maze were intact. In the reversal MWM probe test, KO mice spent more time in the active quadrant (t_18=2.77, p=0.013). In the ASST, KO mice required more trials to reach criterion in the reversal (post-hoc p=0.016) and extra-dimensional shift (post-hoc p<0.001). Acute amphetamine-induced hyperlocomotion was blunted in KO (genotype F_1,35=6.87, p=0.013), while cocaine responses and behavioral sensitization to both drugs were unchanged. Circadian period and core body temperature were normal, but running wheel activity was decreased in KO (F_1,16=11.39, p=0.0039). Sleep architecture showed decreased wake and increased NREM during specific dark-phase hours, with significantly increased slow-wave (delta, 0.5–4.5 Hz) power during NREM in both light (F_48,384=2.5, p<0.001) and dark phases (F_48,384=3.64, p<0.001). Transcriptomic analysis at high stringency (adj. p<0.05, |logFC|≥1) revealed relatively few DEGs per region (range: 12 in VTA to 53 in DG). SV2c was the most upregulated gene in 4 of 6 regions (LC, NAc, VTA, raphe). In situ hybridization confirmed a ~20% increase in SV2c mRNA in the LC of KO mice (t_6=−4.25, p=0.0054). In the CSDS paradigm, SV2c expression was significantly increased in the LC of susceptible mice compared to both control and resilient mice (F_2,10=5.41, p=0.026; CTL vs. SUSC p=0.012, SUSC vs. RES p=0.025).
**Clinical Implications:** This study demonstrates that central NE depletion produces a surprisingly mild baseline phenotype, with anxiolytic- and antidepressant-like effects, enhanced contextual fear memory, impaired cognitive flexibility on the ASST, and deeper NREM sleep. The findings suggest that NE plays a critical role in stress modulation and cognitive flexibility rather than in baseline mood or spatial memory. The identification of SV2c as a consistently upregulated gene in NE-depleted brains and its specific elevation in stress-susceptible mice points to SV2c as a potential novel biomarker or therapeutic target for stress-related disorders. The VMAT2^DBHcre^ model provides a valuable tool for dissecting central versus peripheral NE functions and for identifying compensatory mechanisms that could be leveraged therapeutically in conditions involving NE dysregulation, such as depression, anxiety, PTSD, and neurodegenerative diseases.